From cooperation to collapse: systemic failure in liver disease through a sociological lens
Sections
Open Access Review
From cooperation to collapse: systemic failure in liver disease through a sociological lens

Affiliation:

1Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

2Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

These authors contributed equally to this work.

ORCID: https://orcid.org/0000-0003-4605-2423

Junyu Wang
1,2†

Affiliation:

3Department of Sociology, Faculty of Behavioral and Social Sciences, University of Groningen, 9700 RB Groningen, The Netherlands

These authors contributed equally to this work.

ORCID: https://orcid.org/0009-0006-4902-5294

Jingting Lei
3†

Affiliation:

2Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

Email: m.c.harmsen@umcg.nl

ORCID: https://orcid.org/0000-0002-7128-2741

Martin C. Harmsen
2*

Affiliation:

1Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

Email: a.j.moshage@umcg.nl

ORCID: https://orcid.org/0000-0002-4764-0246

Han Moshage
1*

Explor Dig Dis. 2025;4:100580 DOl: https://doi.org/10.37349/edd.2025.100580

Received: March 27, 2025 Accepted: June 06, 2025 Published: July 08, 2025

Academic Editor: Ina Bergheim, University of Vienna, Austria

Abstract

The liver operates as a highly coordinated microsystem, where various liver cell types engage in dynamic interactions to maintain homeostasis. This intercellular cooperation resembles sociological models of sustainable cooperation, encompassing mechanisms such as resource sharing, communication networks, and conflict resolution. However, both in biology and sociology, cooperation can break down due to external pressures and self-serving behaviors. In metabolic dysfunction-associated steatotic liver disease (MASLD), chronic metabolic stress disrupts this equilibrium, leading to endothelial dysfunction, immune overactivation, and fibrosis—akin to sociological models of systemic collapse. A common model in sociology, Hardin’s Tragedy of the Commons, describes how individuals overexploit shared resources when acting in self-interest, ultimately leading to resource depletion. Similarly, under metabolic stress, hepatic cells prioritize short-term survival by increasing lipid storage, inflammatory signaling, and extracellular matrix (ECM) production. This self-serving response, much like free-riding in societal systems, exacerbates dysfunction, reinforcing a cycle of fibrosis and organ failure. Moreover, the failure in MASLD extends beyond the liver itself. The liver’s cooperative role is integral to its participation in inter-organ axes, including those with the cardiovascular, gut, brain, and kidney systems. While the analogy has limitations—cells do not possess intent as humans do—the fundamental principle of cooperation breakdown leading to systemic instability holds across disciplines. An interdisciplinary approach integrating biological and sociological insights offers novel perspectives for therapeutic innovation. Sociological frameworks provide concepts such as incentive structures and collective action, which can be applied to cellular behavior. By restoring cooperative cellular networks, therapies like extracellular vesicle (EV) treatment, ECM remodeling, and receptor (ant)agonists mimic interventions in social systems that rebuild trust and sustainability. This review explores how biological and sociological models of cooperation breakdown align and how regenerative medicine can leverage these insights to develop strategies that restore cellular equilibrium and halt disease progression.

Keywords

Liver homeostasis, sustainable cooperation, metabolic dysfunction-associated steatotic liver disease, intercellular communication, sociological models

Introduction

Sustainable cooperation, a key concept in sociology, refers to the persistence of mutually beneficial interactions among individuals or groups over time [14]. It is often analyzed through frameworks such as game theory, which models strategic decision-making among agents, mutualism, which describes cooperative relationships where all parties gain benefits, and collective action, which explores how individuals coordinate efforts to achieve shared goals despite potential conflicts of interest [3, 5, 6]. These principles, commonly used to understand human societies and ecosystems, can also provide insight into cellular interactions within complex biological systems [24, 68].

The liver, a highly organized and dynamic organ, relies on intricate communication networks among its resident cells to maintain homeostasis [810]. Hepatocytes, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs), cholangiocytes, and other innate immune cells engage in continuous cross-talk through signaling molecules, extracellular vesicles (EVs), and direct cell-cell interactions [10, 11]. Much like cooperative networks in human societies, these cells dynamically regulate each other’s functions, balancing regeneration, immune responses, and metabolic activities [10, 12]. However, when this cooperation breaks down—due to persistent stress, inflammation, or metabolic dysfunction—it can lead to disease progression, such as in metabolic dysfunction-associated steatotic liver disease (MASLD) [9, 10, 13, 14].

The idea that health depends on physiological harmony among body parts or organs has a long history, dating back to classical thinkers like Galen. Our aim is not to restate this holistic principle but to offer an updated, cross-disciplinary framework that connects modern sociological theories, such as the Tragedy of the Commons, institutional failure, and self-repair models, to specific disruptions in hepatic cell-cell communication seen in MASLD. This approach extends classical concepts by integrating contemporary systems biology with regenerative medicine and social theory.

In doing so, we go beyond metaphors by mapping concrete therapeutic strategies [e.g., EV-mediated immune recalibration, extracellular matrix (ECM)-based structural normalization, receptor (ant)agonist-driven metabolic reprogramming] onto sociological mechanisms such as conflict mediation, trust restoration, and collective-action repair. These analogies not only provide a conceptual lens for understanding intercellular dysfunction but also provide information on targeted interventions aimed at restoring hepatic cooperation.

This review, therefore, seeks to synthesize sociological and biomedical insights into a cohesive model of systemic breakdown and repair. By drawing parallels between sociological cooperation models and hepatic cellular networks, we aim to provide a novel perspective on the mechanisms governing liver homeostasis and disease development. Ultimately, we propose that viewing MASLD through this interdisciplinary lens may yield new therapeutic avenues by addressing the fundamental breakdown of cooperation within and outside the liver.

The liver as a cooperative microsystem

The liver functions as a highly coordinated microsystem, where multiple cell types interact dynamically to maintain homeostasis (Figure 1) [14, 15]. This balance is achieved through a continuous exchange of signals, nutrients, and metabolic byproducts among hepatocytes, LSECs, HSCs, KCs, and other immune cells [10, 15]. Each of these cell types plays a distinct yet interdependent role, mirroring the principles of mutualism in sociological theory, where different actors contribute to the stability of a shared system [9, 10, 16].

The intercellular communication and cooperation between liver cells under healthy and diseased conditions. Healthy condition: ① The dynamic crosstalk between hepatocytes and liver sinusoidal endothelial cells (LSECs) maintains liver metabolism, regeneration, and immune tolerance, ensuring a stable and functional hepatic microenvironment; ② The hepatocytes and quiescent hepatic stellate cells (qHSCs) engage in mutual regulation through paracrine signaling and extracellular matrix (ECM) maintenance, ensuring liver structure, metabolic balance, and protection from injury; ③ Functional LSECs maintain HSC quiescence through paracrine signaling, nitric oxide production, and vitamin A transfer, while qHSCs support the structural and functional integrity of LSECs; ④ The crosstalk between functional LSECs and Kupffer cells (KCs) in a healthy liver involves a balance of immunoregulation, anti-inflammatory signaling, and clearance of debris and endotoxins. LSECs maintain the immunotolerant environment by suppressing excessive KC activation via nitric oxide, anti-inflammatory cytokines, and antigen presentation. KCs, in turn, support LSEC function by clearing toxins and secreting growth factors, ensuring the stability of the liver sinusoidal microenvironment. Diseased condition: ① Chronic parenchymal cell damage; ② It leads to the release of danger-associated molecular patterns (DAMPs) and pro-inflammatory mediators by KCs; ③ LSECs capillarization; ④ KCs are activated and continuously secrete inflammatory mediators; ⑤ qHSCs are stimulated by DAMPs to transform into activated HSCs (aHSCs). They start to exhibit a state of rapid proliferation and secreting high amounts of ECM, triggering inflammation and fibrosis

Hepatocytes, the primary parenchymal cells of the liver, regulate metabolic functions, detoxification, and protein synthesis [17]. They rely on LSECs for nutrient and oxygen exchange, as well as on KCs for immune surveillance [9, 18]. HSCs contribute to ECM remodeling and respond to injury by supporting tissue repair, while cholangiocytes manage bile production and transport [19, 20]. In a healthy liver, these cells engage in reciprocal regulation, adjusting their behavior in response to environmental and physiological changes [9, 10, 21]. This cooperative equilibrium prevents excessive inflammation, fibrosis, or metabolic dysfunction [11, 21].

Sociologist Elinor Ostrom’s work on common-pool resource management provides an insightful parallel to liver cell cooperation [1, 22, 23]. Ostrom argued that sustainable resource management relies on collective governance, where individuals follow self-regulated rules to maintain long-term benefits for the group [24]. Similarly, liver cells maintain a self-organized regulatory network, where no single cell type dominates, but instead, each contributes to the stability of the system [9]. For instance, hepatocytes produce metabolic substrates that KCs and LSECs utilize, while LSECs secrete angiocrine factors that regulate HSC quiescence, preventing excessive fibrosis [9, 10]. When this delicate balance is disrupted—for example, due to chronic lipid overload, inflammation, or oxidative stress—cellular cooperation deteriorates, leading to pathological changes in MASLD, including hepatocyte dysfunction, LSEC capillarization, and uncontrolled HSC activation [10, 13].

By viewing the liver as a cooperative system governed by mutualistic interactions, we can better understand the mechanisms that sustain hepatic function under normal conditions and how their failure contributes to disease progression. This perspective also suggests that restoring cooperative dynamics, rather than targeting individual cell types in isolation, may be a more effective therapeutic approach for MASLD and other chronic liver diseases.

Mechanisms of cellular cooperation

The liver operates as a highly coordinated system, where cellular interactions ensure homeostasis through specialized roles, signaling networks, and regulatory mechanisms (Figure 2) [911]. These cooperative behaviors resemble social systems, where resource sharing, communication, and conflict resolution sustain collective stability [1, 4].

Regulatory mediators of intercellular communication between liver cells under physiological and pathological conditions. HGF: hepatocyte growth factor; RSPO3: R-spondin 3; MASP1: mannan-binding lectin serine protease 1; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; ITGβ1: integrin β1; IGFBP7: insulin-like growth factor-binding protein-7; ADAMTS1: ADAM metallopeptidase with thrombospondin type 1 motif 1; S1P: sphingosine 1-phosphate; TPM1: tropomyosin-1; SphK1: sphingosine kinase 1; TLR3: toll-like receptor-3; VNN-1: pantetheinase; VEGF: vascular endothelial growth factor; CXCL10: C-X-C motif chemokine 10; LSECs: liver sinusoidal endothelial cells; HSCs: hepatic stellate cells

Resource sharing and division of labor

In a functional liver, different cell types specialize in distinct yet interdependent roles, much like the division of labor in social economies [25]. LSECs play a crucial role in regulating nutrient and oxygen exchange between the bloodstream and hepatocytes, acting as metabolic gatekeepers [26]. Hepatocytes, in turn, process these nutrients and synthesize proteins, while HSCs contribute to ECM homeostasis and tissue repair [17, 19]. KCs, cholangiocytes, and other immune cells also fulfill essential roles in immune surveillance and bile production, respectively [18, 27].

This specialization enhances efficiency, much like Adam Smith’s concept of division of labor, where task specialization increases productivity [28]. In economics, decentralized specialization allows societies to optimize resource use—similarly, in the liver, cellular division of labor prevents metabolic overload and ensures rapid adaptation to changing physiological demands [28, 29]. However, in conditions such as MASLD, hepatocyte lipid accumulation and metabolic dysfunction disrupt this balance, leading to excessive stress on other liver cells, much like economic systems failing due to inefficient resource distribution [3032].

Signaling and communication networks

Effective cooperation requires continuous communication among liver cells, primarily mediated through EVs, cytokines, and direct cell-cell interactions [9, 11]. EVs, which carry bioactive molecules such as microRNAs and proteins, act as informational messengers, enabling cross-talk among liver cell types [11]. This resembles knowledge-sharing networks in social systems, where decentralized communication fosters stability and adaptability [33].

From a network theory perspective, the liver’s intercellular signaling resembles distributed information processing, where no single node (cell type) controls the entire system [34, 35]. Instead, multiple pathways ensure redundancy and adaptability [35]. For instance, LSECs secrete factors that keep HSCs in a quiescent state, while KCs modulate immune responses through cytokine signaling [27, 36]. When this informational balance is disrupted, such as in chronic inflammation, EV-mediated signals may shift towards pro-fibrotic or inflammatory cues, reinforcing pathological changes in MASLD [37]. This parallels failures in decentralized networks, where misinformation or communication breakdowns can destabilize entire systems [33, 34].

Conflict resolution and self-regulation

While cooperation is essential, conflict naturally arises in both social and biological systems. KCs and other immune cells act as regulatory agents, preventing excessive damage by clearing pathogens and apoptotic cells [18, 27, 38]. However, in conditions like MASLD, chronic stress, and lipid accumulation can lead to the overactivation of KCs, resulting in excessive inflammation and hepatocyte injury [27, 39].

This process mirrors challenges in social cooperation models, where systems must prevent exploitation and free-riding (as described in public goods theory) [1, 24]. In well-functioning societies, regulatory mechanisms such as legal frameworks and social norms prevent individuals from exploiting collective resources [1, 40]. Similarly, in the liver, negative feedback loops normally restrain immune activation, preventing excessive tissue damage [41]. However, in disease states, this self-regulation fails, leading to chronic inflammation, fibrosis, and loss of liver function [42, 43].

Breakdown of sustainable cooperation in MASLD

In a healthy liver, intercellular cooperation ensures homeostasis through resource sharing, communication, and self-regulation [9, 10]. However, in MASLD, prolonged metabolic stress disrupts this balance, leading to loss of LSEC integrity, HSC overactivation, chronic inflammation, and even hepatocyte death (Figures 1 and 2) [20, 30, 32, 39]. These pathological shifts resemble sociological collapse models, where the breakdown of cooperation destabilizes entire systems [44, 45].

Loss of LSEC integrity: disrupted nutrient exchange and pro-inflammatory signals

LSECs play a central role in maintaining metabolic homeostasis by regulating nutrient and oxygen exchange, as well as preventing excessive immune activation [26, 4648]. In early MASLD, chronic lipid accumulation and oxidative stress induce capillarization of LSECs, where they lose their fenestrae and adopt a more rigid, vascular-like phenotype [47]. This impairs nutrient exchange, leading to hepatocyte stress and metabolic dysregulation [47, 49]. Additionally, dysfunctional LSECs secrete pro-inflammatory signals, amplifying KC activation and perpetuating a cycle of inflammation [50].

This failure parallels Hardin’s “Tragedy of the Commons” (1968), a sociological model describing how unregulated resource consumption leads to collective system collapse [44, 51]. In MASLD, excessive lipid accumulation overwhelms hepatocytes, forcing LSECs to adapt maladaptively, much like how overexploitation of natural resources leads to environmental degradation [5255]. Without intervention, this process escalates, further destabilizing the hepatic microenvironment [55].

HSC overactivation: fibrosis and loss of liver plasticity

HSCs are normally quiescent and serve as the primary storage site for vitamin A in the liver, storing it in lipid droplets and regulating retinoid metabolism [20, 56]. In their resting state, HSCs contribute to liver homeostasis not only by maintaining ECM balance and providing structural support [19, 57], but also by promoting hepatocyte metabolism and regeneration through R-spondin 3 (RSPO3), an HSC-enriched modulator of WNT signaling [58]. However, in MASLD, chronic LSEC dysfunction and inflammatory signals drive persistent HSC activation, leading to excessive ECM deposition (fibrosis) [48, 59]. Over time, this reduces liver plasticity, impairing its ability to regenerate and respond to metabolic demands [21].

This breakdown of regulation mirrors sociological models of institutional failure, where self-organized systems collapse due to unchecked exploitation and rigidity [60, 61]. As Ostrom (1990) noted, sustainable governance relies on adaptive mechanisms that prevent the overuse of shared resources [1, 62, 63]. In the liver, HSCs should remain responsive to changing conditions, balancing ECM production and degradation [20]. However, in MASLD, the feedback loops that normally restore equilibrium fail, leading to a pathological fibrotic state akin to a society trapped in irreversible economic or environmental decline [20, 44, 64].

KC dysregulation: from immune surveillance to chronic inflammation

KCs are the liver’s resident macrophages, responsible for immune surveillance, clearance of apoptotic cells, and tolerance to gut-derived microbial products [27, 65]. However, in MASLD, excessive lipid exposure and oxidative stress trigger KC reprogramming into a pro-inflammatory phenotype, characterized by excessive secretion of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) [18, 6567].

Chronic KC activation propagates hepatocyte injury and exacerbates fibrosis by stimulating HSC activation [6769]. This loss of immune tolerance resembles sociological models of governance failure, where institutions meant to mediate conflicts instead contribute to systemic instability [70, 71]. In this analogy, KCs function like regulatory bodies that, when overwhelmed by excessive stimuli, shift from maintaining order to perpetuating dysfunction [27].

Hepatocyte dysfunction: metabolic overload and loss of adaptability

Hepatocytes, as the liver’s primary metabolic units, regulate lipid metabolism, glucose homeostasis, and detoxification [17]. Under physiological conditions, they maintain energy balance by coordinating with LSECs, KCs, and HSCs [9, 10]. However, in MASLD, sustained lipid accumulation and oxidative stress impair mitochondrial function, reducing ATP production and increasing reactive oxygen species (ROS) generation [30, 32].

This metabolic overload forces hepatocytes into maladaptive responses, including excessive triglyceride storage, apoptosis, and lipid peroxidation [17]. Eventually, these changes trigger hepatocyte ballooning and cell death, further exacerbating inflammation and fibrosis [72, 73]. The hepatocyte dysfunction in MASLD resembles economic collapse models, where excessive short-term resource consumption leads to irreversible decline [44, 74]. Just as economies suffer when industries prioritize immediate gains over long-term stability, hepatocytes under metabolic stress prioritize lipid accumulation at the cost of overall liver function [75, 76].

The liver as a failing commons: a model of systemic breakdown

The liver in MASLD can be viewed as a failing common, where cooperative cellular behaviors that once sustained function are disrupted by metabolic stress, inflammation, and fibrosis [14, 39]. Just as societies collapse when individuals act in short-term self-interest at the expense of long-term stability, hepatocytes, LSECs, KCs, and HSCs in MASLD shift from cooperation to self-preservation, leading to organ dysfunction [11, 77]. This sociological perspective not only explains why MASLD progresses but also highlights potential therapeutic strategies: restoring LSEC function, reducing HSC activation, and modulating KC-mediated inflammation could help reestablish cellular cooperation. By addressing the breakdown of intercellular coordination, rather than just targeting isolated pathological features, we may identify more effective interventions to prevent liver failure in MASLD.

Beyond the liver: cross-organ cooperation and systemic disruption in MASLD

While much attention in MASLD research has focused on hepatocellular dysfunction, the progression and prognosis of the disease are deeply influenced by inter-organ dynamics [78, 79]. The liver does not operate in isolation but is embedded in a broader physiological network involving the gut, cardiovascular system, and other organs, each with tightly regulated feedback loops [7880]. Disruption in this inter-organ “society” can exacerbate systemic failure, mirroring how the collapse of one sector in a sociopolitical system often cascades into wider instability, resulting not only in hepatic dysfunction but also in widespread consequences such as cardiovascular disease, cognitive disturbance, and gut-derived metabolic stress.

Liver–cardiovascular coordination: a fatal disintegration

Cardiovascular disease is the leading cause of mortality in patients with MASLD [81, 82]. This reality underscores the pathophysiological entanglement between hepatic dysfunction and cardiovascular risk [83]. Hepatic steatosis and inflammation promote atherogenesis through increased secretion of pro-inflammatory cytokines, altered lipid metabolism, and insulin resistance [84]. Conversely, systemic hypertension and endothelial dysfunction can amplify hepatic injury by impairing blood flow and oxygen delivery to liver tissue [8185]. Rather than coincidental comorbidities, MASLD and cardiovascular disease are co-evolving and mutually reinforcing conditions [14]. Their bidirectional influence reflects a collapse in systemic cooperation, where dysfunction in one organ destabilizes another, much like a financial crisis rippling through interconnected economic institutions. This breakdown underscores the need for therapeutic strategies that address the broader network of inter-organ dynamics, not just isolated hepatic pathology.

Liver–gut axis: microbial disruption and information breakdown

The gut microbiome plays a pivotal role in MASLD, functioning as a communication hub that links dietary inputs, metabolic regulation, and immune signaling [86]. In healthy states, the liver and gut maintain a cooperative relationship via the portal circulation, where microbial metabolites, such as short-chain fatty acids and bile acids, help modulate hepatic metabolism and immune tone [80, 87]. This bidirectional exchange preserves homeostasis and ensures that signals from the gut are appropriately interpreted by hepatic cells. However, gut dysbiosis disrupts this finely tuned relationship [80, 88]. Increased intestinal permeability (“leaky gut”) permits the translocation of bacterial endotoxins such as lipopolysaccharide (LPS), alongside microbial-associated molecular patterns (MAMPs), into the liver [89]. These stressors directly interfere with KC homeostasis and disrupt hepatocyte lipid metabolism, triggering chronic low-grade inflammation and metabolic dysfunction [90, 91]. Additionally, dysbiosis alters bile acid signaling, further impairing hepatic regulatory circuits [80, 92]. Collectively, these effects make gut dysbiosis a powerful upstream disruptor of intercellular communication in the liver, exacerbating MASLD progression [80]. From a sociological perspective, the gut microbiome can be likened to a decentralized network of informants and producers whose biochemical outputs influence central governance, represented here by the liver. When this network becomes dysregulated, distorted messages flood the system, mirroring the societal consequences of disinformation. As in political systems destabilized by misinformation, the liver’s capacity to coordinate and respond rationally is compromised, accelerating systemic breakdown [93]. Therapeutically, restoring liver–gut cooperation involves recalibrating this informational axis. Interventions targeting the microbiome, such as prebiotics, probiotics, postbiotics, or microbial-derived EVs, aim to reduce inflammatory inputs and restore signal fidelity [94]. By reestablishing a healthier microbial environment, these strategies seek to interrupt the pathological feedback loop and promote cooperative stability across the liver–gut axis.

Liver–brain axis: neuroimmune disruption and metabolic feedback loops

The liver–brain axis is increasingly recognized as a bidirectional communication pathway involved in regulating appetite, cognition, and systemic homeostasis [95]. The liver influences central nervous system (CNS) function through cytokines, metabolic hormones [e.g., insulin, leptin, fibroblast growth factor 21 (FGF21)], and detoxification of neuroactive substances [96, 97]. In MASLD, disrupted hepatic signaling and chronic low-grade inflammation can alter vagal tone, impair neuroendocrine feedback, and contribute to neuroinflammation, cognitive impairment, and mood disorders [96, 98]. This systemic crosstalk breakdown parallels sociological dysfunction, where impaired “policy implementation” (liver signaling) undermines executive function (brain regulation). Thus, the liver–brain axis represents another site of inter-organ cooperation whose destabilization amplifies MASLD’s multisystem burden.

Liver–kidney axis: metabolic and detoxification interdependence

The liver and kidneys cooperate in key metabolic functions, including ammonia detoxification, glucose homeostasis, and xenobiotic clearance [99]. In MASLD, particularly in advanced stages with fibrosis or cirrhosis, this interdependence is strained [99, 100]. Systemic inflammation, disrupted bile acid metabolism, and impaired renal perfusion contribute to hepatorenal dysfunction and cardiorenal complications [99101]. Analogous to a destabilized central bank burdening a dependent economy, hepatic failure transfers metabolic stress to the kidneys, accelerating their decline and reinforcing systemic collapse. The liver–kidney axis thus exemplifies how inter-organ cooperation, once disrupted, can amplify disease progression across organ systems.

Liver–adipose axis: metabolic diplomacy and energy governance

Adipose tissue, particularly visceral fat, is a key regulator of hepatic function through the release of adipokines (e.g., adiponectin, leptin, resistin) and free fatty acids [102, 103]. In MASLD, dysfunctional adipose tissue acts as a metabolic saboteur, contributing to insulin resistance, lipotoxicity, and systemic inflammation [104]. This reflects a breakdown in metabolic diplomacy, where formerly cooperative energy reservoirs now release antagonistic signals that destabilize hepatic homeostasis. Sociologically, this resembles a once-productive trading partner devolving into a hostile neighbor, flooding markets (the liver) with toxic goods (lipids and cytokines) and undermining internal regulatory systems.

Liver–skeletal muscle axis: resource allocation and sarcopenic feedback

The liver and skeletal muscle maintain a dynamic partnership in regulating systemic metabolism, particularly in glucose and amino acid homeostasis [105, 106]. Skeletal muscle acts as a major reservoir for glucose disposal and protein storage, while the liver orchestrates gluconeogenesis and nutrient distribution [105, 107, 108]. In the context of MASLD, this inter-organ axis becomes strained. Chronic inflammation, insulin resistance, and altered amino acid metabolism contribute to sarcopenia—a progressive loss of muscle mass and function, which in turn reduces peripheral glucose uptake and increases metabolic burden on the liver [109, 110]. This feedback loop represents a failure in systemic resource allocation, akin to the breakdown of infrastructure-sharing in a complex federation. When skeletal muscle, normally a cooperative energy sink, begins to degrade, it no longer fulfills its role in buffering postprandial glucose or maintaining metabolic stability. The liver, already under lipotoxic and inflammatory pressure, is forced to compensate, worsening hepatocellular stress and accelerating disease progression.

Liver–lung axis: shared inflammatory landscapes and hypoxic burden

Although less frequently discussed, the liver and lungs are deeply interconnected, especially in the context of systemic inflammation and hypoxia [111]. In MASLD, circulating pro-inflammatory cytokines and altered coagulation profiles can affect pulmonary microvasculature, increasing the risk for conditions such as pulmonary hypertension and obstructive sleep apnea [112, 113]. Conversely, chronic hypoxia from lung disease can exacerbate hepatic steatosis and fibrosis through oxidative stress [114, 115]. This reflects a feedback loop where two interdependent systems collapse under shared inflammatory pressure, much like adjacent urban sectors in crisis amplifying each other’s vulnerabilities.

Restoring cooperation: potential therapeutic strategies

MASLD is not merely a condition of individual cellular malfunction but a broader failure of intercellular cooperation within the liver microenvironment [9, 10]. Effective treatment, therefore, must extend beyond correcting isolated pathways to restoring the systemic interactions that underlie hepatic function. Drawing inspiration from sociological models of intervention, such as policy reform, economic restructuring, and conflict mediation, we can conceptualize therapeutic strategies like EVs, ECM, and receptor (ant)agonists as tools for rebuilding cooperative networks among liver cells.

EV therapy: restoring cellular communication and preventing fibrosis

EVs mediate intercellular communication by transferring proteins, microRNAs, and lipids, helping maintain homeostasis under physiological conditions [11, 116]. In MASLD, the loss of functional EV-mediated signaling contributes to inflammation, fibrosis, and metabolic dysfunction [11]. Studies suggest that stem cell-derived EVs or engineered EVs could [117, 118]:

  • Reprogram KCs toward a pro-resolving phenotype, reducing excessive inflammation [27, 65, 119, 120].

  • Suppress HSC activation, preventing excessive ECM deposition [119, 121].

  • Enhance LSEC function, restoring endothelial integrity and nutrient exchange [50, 122, 123].

  • Promoting hepatocyte function recovery and regeneration [124126].

This strategy mirrors sociological policy interventions, where external mediation helps restore communication between conflicting groups, reducing systemic instability [127]. Just as diplomatic negotiations or economic aid can rebuild cooperative structures in failing societies [127, 128], EV therapy aims to reestablish intercellular dialogue, preventing disease progression [129].

ECM hydrogels: providing a supportive microenvironment

A key challenge in MASLD is the loss of liver plasticity due to fibrosis, which limits tissue regeneration [130]. ECM hydrogels offer a biomimetic environment, supporting hepatocyte function, reducing HSC activation, and improving overall tissue remodeling [131133]. By providing a structural and biochemical niche, ECM hydrogels may:

  • Promote hepatocyte regeneration, counteracting metabolic dysfunction [131, 134, 135].

  • Suppress fibrogenic signaling, preventing irreversible ECM accumulation [57, 136].

  • Support LSEC stability, facilitating vascular homeostasis [57, 131, 137, 138].

This approach is analogous to institutional interventions in sociology, where rebuilding public infrastructure (e.g., education systems, healthcare networks) restores long-term societal function [74, 139]. Just as stable institutions enable communities to recover from economic or environmental crises, ECM hydrogels provide a microenvironment that allows hepatocytes and other liver cells to regain functionality [140, 141].

Systemic remodeling based on receptor (ant)agonists: rebuilding liver cooperation

The liver’s ability to maintain homeostasis and respond to injury is governed by complex signaling among diverse cell types. Receptor (ant)agonists, which activate/inhibit specific signaling pathways, can be viewed as molecular analogues to public policy—strategically deployed to incentivize constructive cellular behavior and restore communication. These agents help orchestrate a return to physiological balance, much like systemic reforms aimed at stabilizing failing social institutions.

In the context of MASLD, receptor (ant)agonists that modulate pathways related to metabolism, inflammation, and fibrosis show particular promise. Agonists of the peroxisome proliferator-activated receptors (PPARs), for instance, not only enhance lipid metabolism but also exert anti-inflammatory effects within hepatic cells [142144]. Likewise, glucagon-like peptide-1 (GLP-1) receptor agonists improve hepatocyte survival and reduce hepatic steatosis, contributing to a more resilient and functionally coordinated liver environment [145, 146]. By recalibrating intercellular signaling networks, these agents foster conditions that support collective regeneration and reduce fibrotic progression. Many drugs under investigation have demonstrated promising therapeutic effects by targeting various key pathways in the pathogenesis of MASH (Table 1) [147]. Among these, resmetirom, a thyroid hormone receptor β (THRβ) agonist developed by Madrigal Pharmaceuticals, has become the first and only officially FDA-approved drug for treating MASH [148]. Other candidates, such as PPARs agonists, GLP-1 analogs, and FGF21 analogs, are awaiting approval [147, 149]. Despite these advances, developing pharmacotherapeutics for MASH remains a significant challenge due to the complexity of its pathogenesis, heterogeneity, and the side effects associated with existing treatments [39, 147, 149151]. Metabolic modulators improve insulin sensitivity and reduce hepatic steatosis but are associated with weight gain, while GLP-1 receptor agonists (e.g., liraglutide, semaglutide) and sodium-glucose transport protein 2 (SGLT2) inhibitors enhance glycemic control, reduce liver fat, and demonstrate cardiovascular benefits [147, 152]. Anti-fibrotic agents like obeticholic acid, a FXR agonist, and PPAR agonists like lanifibranor target lipid metabolism and fibrosis but may cause adverse effects like pruritus [147, 149, 153, 154]. Resmetirom and other lipid metabolism modulators have shown efficacy in reducing steatosis and fibrosis during clinical trials, and antioxidants like vitamin E alleviate oxidative stress in some patients. However, their long-term safety and limited clinical efficacy require further evaluation [39, 147, 149].

 List of ongoing pharmacotherapeutic agents in phase II–IV trials for MASH/MASLD

TargetAgentLatest phaseNCTSponsor
Nuclear receptor agonistsTHRβ agonistResmetiromFDA-approvedNCT04951219
NCT04197479
NCT05500222
NCT03900429
Madrigal Pharmaceuticals
VK2809Phase IINCT04173065
NCT02927184
Viking Therapeutics
ASC41NCT05462353FirstWord Pharma
TERN-501NCT05415722Terns Pharmaceuticals
PPARα/δ/γ agonistPioglitazonePhase IVNCT00994682University of Florida
IVA337 (Lanifibranor)Phase IIINCT04849728
NCT05232071
NCT03459079
Inventiva Pharma
ElafibranorNCT02704403
NCT03883607
NCT01694849
Genfit
SaroglitazarPhase IINCT03061721
NCT03863574
Zydus Therapeutics
PemafibrateNCT05327127
NCT03350165
Kowa Research Institute, Inc.
FXR agonistObeticholic acidPhase IIINCT02548351
NCT01265498
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
CilofexorPhase IINCT02854605Gilead Sciences
HPG1860NCT05338034Hepagene (Shanghai) Co., Ltd.
TropifexorNCT02855164
NCT04147195
NCT03517540
Novartis Pharmaceuticals
TERN-101NCT04328077Terns, Inc.
MET409NCT04702490Metacrine, Inc.
CS0159NCT05591079Cascade Pharmaceuticals, Inc
GLP-1R agonistSemaglutideNCT04822181
NCT02970942
Novo Nordisk A/S
LiraglutideNCT01237119
NCT02654665
University of Birmingham
DulaglutidePhase IVNCT03648554Central Hospital, Nancy, France; Eli Lilly and Company
A3 adenosine receptor agonistNamodenosonPhase IIINCT02927314Can-Fite BioPharma
FGF mimeticsFGF21 analogueEfruxiferminPhase IIINCT06215716
NCT06161571
NCT03976401
NCT04767529
Akero Therapeutics
PegozaferminPhase IINCT03486912
NCT03486899
NCT03400163
NCT02413372
89bio
InhibitorsSCD-1 inhibitorAramcholPhase IIINCT04104321Galmed Research and Development
CCR2/CCR5 inhibitorCenicrivirocNCT03028740Tobira Therapeutics, Inc.
Galactin-3 inhibitorBelapectin (GR MD-02)NCT06035874Galectin Therapeutics
ASK1 inhibitorSelonsertibCTR20230344The First Hospital of Jilin University
ACC inhibitorGS-0976NCT02856555Gilead Sciences
MK-4074NCT01431521Merck Sharp & Dohme LLC
FASN inhibitorDenifanstatNCT04906421Sagimet Biosciences Inc.
MPC inhibitorMSDC-0602KNCT02784444Cirius Therapeutics, Inc.
ACLY inhibitorBempedoic acidNCT06035874Medanta - The Medicity
BGT-002CTR20230344The First Hospital of Jilin University
Combination therapyACC inhibitor
DGAT2 inhibitor
PF-05221304
PF-06865571
Phase IIINCT04321031
NCT03248882
NCT03776175
Pfizer
ASK1 inhibitor
ACC inhibitor
FXR agonist
Selonsertib
Firsocostat
Cilofexor
NCT02781584Gilead Sciences
FXR agonist
HMGCR inhibitor
Obeticholic acid
Atorvastatin
NCT02633956Intercept Pharmaceuticals
FXR agonist
GLP-1R agonist
Cilofexor
Semaglutide
NCT03987074Gilead Sciences

MASLD: metabolic dysfunction-associated steatotic liver disease; THRβ: thyroid hormone receptor β; PPARα/δ/γ: peroxisome proliferator-activated receptor α/δ/γ; FXR: farnesoid X receptor; GLP-1R: glucagon-like peptide-1 receptor; FGF: fibroblast growth factor; SCD-1: stearoyl-CoA desaturase-1; CCR2/CCR5: C-C chemokine receptor type 2/5; ASK1: apoptosis signal-regulating kinase 1; ACC: acetyl-CoA carboxylase; FASN: fatty acid synthase; MPC: mitochondrial pyruvate carrier; ACLY: ATP-citrate lyase; DGAT2: diacylglycerol O-acyltransferase 2; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase

The potential of receptor (ant)agonists is further amplified when integrated with EV therapy and ECM hydrogels. EVs—natural carriers of proteins, lipids, and RNAs—facilitate targeted communication between cells and have been shown to modulate fibrosis and support tissue repair. When embedded in ECM hydrogels, which provide mechanical support and biochemical cues, EVs can more effectively propagate regenerative signals across damaged hepatic regions. This integrated approach creates a supportive niche analogous to a social safety net, enabling liver cells to resume cooperative functions and self-organize toward recovery.

Ultimately, systemic remodeling aims not merely to suppress individual pathological pathways but to reestablish a functional and collaborative cellular ecosystem. By treating the liver as a dynamic, self-regulating system—much like a society recovering from systemic breakdown—therapeutic strategies that rebuild intercellular cooperation hold significant potential in addressing the complex, multifactorial nature of MASLD.

Restoring axis integrity through multi-organ coordination

Acknowledging these inter-organ axes demands a therapeutic strategy that transcends hepatocentric approaches. Receptor agonists, EV therapies, and ECM scaffolds must be evaluated not only for their intrahepatic effects but for how they modulate systemic physiology. Targeting the gut microbiome, restoring endothelial function, modulating neuroimmune signaling, and reducing pulmonary inflammation represent coordinated interventions—akin to inter-ministerial policies aimed at restoring national coherence. Viewing MASLD as a systemic disorder opens new pathways for organ-crossing therapies and diagnostic frameworks.

Conclusions

The concept of sustainable cooperation, widely studied in sociology, provides a compelling framework for understanding liver homeostasis and its breakdown in MASLD. Just as societies rely on resource sharing, communication networks, and conflict resolution to maintain stability, the liver depends on cooperative interactions between hepatocytes, LSECs, HSCs, KCs, and cholangiocytes to function effectively. When this cooperation fails, due to metabolic stress, inflammation, and fibrosis, MASLD progresses, resembling sociological models of systemic collapse.

Moreover, the failure in MASLD extends beyond hepatic disintegration. The liver’s cooperative function is embedded in a network of inter-organ axes, including the liver–cardiovascular, liver–gut, liver–brain, liver–lung, liver–kidney, and so on. These axes represent critical lines of metabolic, immune, and neuroendocrine communication. Disruption along these pathways mirrors the collapse of interdependent institutions within a society, where dysfunction in one domain precipitates cascading failures across the whole system. For instance, gut dysbiosis, cardiovascular inflammation, and neuroimmune signaling disruptions not only influence liver pathology but are also amplified by it, creating feedback loops of escalating dysfunction.

By applying sociological theories to liver biology, we gain new perspectives on disease progression and potential interventions. Viewing MASLD as a failure of cellular cooperation shifts the therapeutic focus from merely targeting isolated pathological features to restoring intercellular communication and metabolic balance. Strategies such as EV therapy, ECM hydrogels, and receptor (ant)agonist, which reestablish liver cell interactions, mirror policy interventions in sociology, where external support can stabilize failing systems.

This interdisciplinary perspective—linking systems biology, network theory, and cooperative game theory with sociological models of governance and collapse—opens new avenues for research. Future efforts should prioritize restoring cooperative equilibrium not only at the cellular level but also across the organ axes that define the body’s systemic integrity. In doing so, we may move closer to therapies that don’t just treat liver disease, but reestablish the inter-organ harmony essential to long-term health.

Abbreviations

ECM: extracellular matrix

EVs: extracellular vesicles

FGF21: fibroblast growth factor 21

GLP-1: glucagon-like peptide-1

HSCs: hepatic stellate cells

KCs: Kupffer cells

LSECs: liver sinusoidal endothelial cells

MASLD: metabolic dysfunction-associated steatotic liver disease

PPARs: peroxisome proliferator-activated receptors

THRβ: thyroid hormone receptor β

Declarations

Acknowledgments

During the preparation of this work, the authors used GPT-4o (San Francisco, USA) in order to improve language. After using this tool/service, all authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Author contributions

JW and JL: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. MCH and HM: Validation, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

Prof. Han Moshage is an Associate Editor of Exploration of Digestive Diseases. However, he was not involved in any aspect of the peer review or editorial decision-making process for this manuscript. The other authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This project is financially supported by the China Scholarship Council, File No. [202006250036] (J.W.) & No. [202106200024] (J.L.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

© The Author(s) 2025.

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Ostrom E. A general framework for analyzing sustainability of social-ecological systems. Science. 2009;325:41922. [DOI] [PubMed]
Giardini F, Wittek R. Gossip, reputation, and sustainable cooperation: Sociological foundations. In: Giardini F, Wittek R, editors. The Oxford Handbook of Gossip and Reputation. Oxford University Press; 2019. pp. 21–46. [DOI]
Kirgil ZM, Wittek R. Cooperation sustainability in small groups: Exogenous and endogenous dynamics of the sustainability of cooperation. Ration Soc. 2023;36:93121. [DOI]
Takács K, Gross J, Testori M, Letina S, Kenny AR, Power EA, et al. Networks of reliable reputations and cooperation: a review. Philos Trans R Soc Lond B Biol Sci. 2021;376:20200297. [DOI] [PubMed] [PMC]
Quan J, Cui S, Wang X. Cooperation dynamics in multi-issue repeated social dilemma games with correlated strategy. Phys Rev E. 2024;110:024307. [DOI] [PubMed]
Lejano R, Davos C. Cooperative Solutions for Sustainable Resource Management. Environ Manage. 1999;24:16775. [DOI] [PubMed]
Archetti M, Pienta KJ. Cooperation among cancer cells: applying game theory to cancer. Nat Rev Cancer. 2019;19:1107. [DOI] [PubMed] [PMC]
Gong L, Gao J, Cao M. Evolutionary game dynamics for two interacting populations in a co-evolving environment. In: Proceedings of the 2018 IEEE Conference on Decision and Control (CDC); 2018 Dec 17–19; Miami, FL, USA. Piscataway (NJ): IEEE; 2018. pp. 3535–40. [DOI]
Su J, Song Y, Zhu Z, Huang X, Fan J, Qiao J, et al. Cell-cell communication: new insights and clinical implications. Signal Transduct Target Ther. 2024;9:196. [DOI] [PubMed] [PMC]
Kmieć Z. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol. 2001;161:IIIXIII, 1. [DOI] [PubMed]
Wu Z, Xia M, Serna Salas S, Trillos-Almanza MC, Martinez Aguilar M, Arroyave-Ospina JC, et al. Extracellular vesicles in metabolic dysfunction associated fatty liver disease: mechanisms, diagnostic and therapeutic implications. Explor Dig Dis. 2022;1:420. [DOI]
Ma Z, Zuo T, Frey N, Rangrez AY. A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation. Signal Transduct Target Ther. 2024;9:237. [DOI] [PubMed] [PMC]
Lim JS, Mietus-Snyder M, Valente A, Schwarz J, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010;7:25164. [DOI] [PubMed]
Zheng H, Sechi LA, Navarese EP, Casu G, Vidili G. Metabolic dysfunction-associated steatotic liver disease and cardiovascular risk: a comprehensive review. Cardiovasc Diabetol. 2024;23:346. [DOI] [PubMed] [PMC]
Stanger BZ. Cellular homeostasis and repair in the mammalian liver. Annu Rev Physiol. 2015;77:179200. [DOI] [PubMed] [PMC]
Dixit T. A synthesis of coevolution across levels of biological organization. Evolution. 2024;78:21120. [DOI] [PubMed]
Zhou Z, Xu M, Gao B. Hepatocytes: a key cell type for innate immunity. Cell Mol Immunol. 2016;13:30115. [DOI] [PubMed] [PMC]
Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol. 2016;13:31627. [DOI] [PubMed] [PMC]
Yin C, Evason KJ, Asahina K, Stainier DYR. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest. 2013;123:190210. [DOI] [PubMed] [PMC]
Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397411. [DOI] [PubMed]
Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, et al. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther. 2025;10:63. [DOI] [PubMed] [PMC]
Saunders FP. The promise of common pool resource theory and the reality of commons projects. Int J Commons. 2014;8:63656. [DOI]
Wheeler B, Williams O, Meakin B, Chambers E, Beresford P, O’Brien S, et al. Exploring Elinor Ostrom’s principles for collaborative group working within a user-led project: lessons from a collaboration between researchers and a user-led organisation. Res Involv Engagem. 2024;10:15. [DOI] [PubMed] [PMC]
Haryanto T, van Zeben J, Purnhagen K. Ostrom’s Design Principles as Steering Principles for Contractual Governance in “Hotbeds”. For Soc. 2022;6:175201. [DOI]
Damania A, Jain E, Kumar A. Advancements in in vitro hepatic models: application for drug screening and therapeutics. Hepatol Int. 2014;8:2338. [DOI] [PubMed]
McConnell MJ, Kostallari E, Ibrahim SH, Iwakiri Y. The evolving role of liver sinusoidal endothelial cells in liver health and disease. Hepatology. 2023;78:649669. [DOI] [PubMed] [PMC]
Liu Y, Tian F, Shan J, Gao J, Li B, Lv J, et al. Kupffer Cells: Important Participant of Hepatic Alveolar Echinococcosis. Front Cell Infect Microbiol. 2020;10:8. [DOI] [PubMed] [PMC]
Powell SG. Specialization, teamwork, and production efficiency. Int J Prod Econ. 2000;67:20518. [DOI]
Yaman A, Leibo JZ, Iacca G, Lee SW. The emergence of division of labour through decentralized social sanctioning. Proc Biol Sci. 2023;290:20231716. [DOI] [PubMed] [PMC]
Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62:S4764. [DOI] [PubMed]
Hutchison AL, Tavaglione F, Romeo S, Charlton M. Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): Beyond insulin resistance. J Hepatol. 2023;79:152441. [DOI] [PubMed]
Yeh M, Yu M. From nonalcoholic steatohepatitis, metabolic dysfunction-associated fatty liver disease, to steatotic liver disease: Updates of nomenclature and impact on clinical trials. Clin Mol Hepatol. 2023;29:96972. [DOI] [PubMed] [PMC]
Bernstein ES, Shore JC, Jang AJ. Network Centralization and Collective Adaptability to a Shifting Environment. Organ Sci. 2023;34:206496. [DOI]
Nilsson A, Peters JM, Meimetis N, Bryson B, Lauffenburger DA. Artificial neural networks enable genome-scale simulations of intracellular signaling. Nat Commun. 2022;13:3069. [DOI] [PubMed] [PMC]
Koseska A, Bastiaens PI. Cell signaling as a cognitive process. EMBO J. 2017;36:568582. [DOI] [PubMed] [PMC]
Van Riet S, Julien A, Atanasov A, Nordling Å, Ingelman-Sundberg M. The role of sinusoidal endothelial cells and TIMP1 in the regulation of fibrosis in a novel human liver 3D NASH model. Hepatol Commun. 2024;8:e0374. [DOI] [PubMed] [PMC]
Wang J, Li J, Buist-Homan M, Harmsen MC, Moshage H. Extracellular vesicle-dependent crosstalk between hepatic stellate cells and Kupffer cells promotes their mutual activation. Biochim Biophys Acta Mol Basis Dis. 2025;1871:167914. [DOI] [PubMed]
Feng M, Ding J, Wang M, Zhang J, Zhu X, Guan W. Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution. Int J Biol Sci. 2018;14:10331040. [DOI] [PubMed] [PMC]
Portincasa P, Khalil M, Mahdi L, Perniola V, Idone V, Graziani A, et al. Metabolic Dysfunction-Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options. Int J Mol Sci. 2024;25:5640. [DOI] [PubMed] [PMC]
United Nations Women; Cookson TP, Fuentes L, Kuss MK, Bitterly J. UN Women Discussion Paper Series. 2023. [DOI]
Zhang N, Yao H, Zhang Z, Li Z, Chen X, Zhao Y, et al. Ongoing involvers and promising therapeutic targets of hepatic fibrosis: The hepatic immune microenvironment. Front Immunol. 2023;14:1131588. [DOI] [PubMed] [PMC]
Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest. 2017;127:5564. [DOI] [PubMed] [PMC]
Tanwar S, Rhodes F, Srivastava A, Trembling PM, Rosenberg WM. Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C. World J Gastroenterol. 2020;26:10933. [DOI] [PubMed] [PMC]
Crutchfield P. Societal Collapse and Intergenerational Disparities in Suffering. Neuroethics. 2022;15:27. [DOI] [PubMed] [PMC]
Schunck F, Wiedermann M, Heitzig J, Donges JF. A Dynamic Network Model of Societal Complexity and Resilience Inspired by Tainter’s Theory of Collapse. Entropy (Basel). 2024;26:98. [DOI] [PubMed] [PMC]
Iwakiri Y. Unlocking the role of liver sinusoidal endothelial cells: Key players in liver fibrosis: Editorial on “Liver sinusoidal endothelial cell: An important yet often overlooked player in the liver fibrosis”. Clin Mol Hepatol. 2024;30:6736. [DOI] [PubMed] [PMC]
Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D, et al. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J Hepatol. 2017;66:21227. [DOI] [PubMed]
Xu M, Wang X, Zou Y, Zhong Y. Key role of liver sinusoidal endothelial cells in liver fibrosis. Biosci Trends. 2017;11:1638. [DOI] [PubMed]
Qu J, Wang L, Li Y, Li X. Liver sinusoidal endothelial cell: An important yet often overlooked player in the liver fibrosis. Clin Mol Hepatol. 2024;30:30325. [DOI] [PubMed] [PMC]
Lafoz E, Ruart M, Anton A, Oncins A, Hernández-Gea V. The Endothelium as a Driver of Liver Fibrosis and Regeneration. Cells. 2020;9:929. [DOI] [PubMed] [PMC]
Hardin G. The tragedy of the commons. The population problem has no technical solution; it requires a fundamental extension in morality. Science. 1968;162:12438. [PubMed]
Geng Y, Arroyave-Ospina JC, Buist-Homan M, Plantinga J, Olinga P, Reijngoud D, et al. Differential effects of oleate on vascular endothelial and liver sinusoidal endothelial cells reveal its toxic features in vitro. J Nutr Biochem. 2023;114:109255. [DOI] [PubMed]
Arroyave-Ospina JC, Buist-Homan M, Schmidt M, Moshage H. Protective effects of caffeine against palmitate-induced lipid toxicity in primary rat hepatocytes is associated with modulation of adenosine receptor A1 signaling. Biomed Pharmacother. 2023;165:114884. [DOI] [PubMed]
Arroyave-Ospina JC, Wu Z, Geng Y, Moshage H. Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy. Antioxidants (Basel). 2021;10:174. [DOI] [PubMed] [PMC]
Geng Y, Faber KN, Meijer VEd, Blokzijl H, Moshage H. How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease? Hepatol Int. 2021;15:2135. [DOI] [PubMed] [PMC]
Horn P, Tacke F. Metabolic reprogramming in liver fibrosis. Cell Metab. 2024;36:143955. [DOI] [PubMed]
Badylak SF, Freytes DO, Gilbert TW. Extracellular matrix as a biological scaffold material: Structure and function. Acta Biomater. 2009;5:113. [DOI] [PubMed]
Sugimoto A, Saito Y, Wang G, Sun Q, Yin C, Lee KH, et al. Hepatic stellate cells control liver zonation, size and functions via R-spondin 3. Nature. 2025;640:75261. [DOI] [PubMed] [PMC]
DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology. 2015;61:17406. [DOI] [PubMed] [PMC]
von Billerbeck S. Sociological institutionalism. In: Oksamytna K, Karlsrud J, editors. United Nations peace operations and International Relations theory. Manchester: Manchester University Press; 2020. pp. 91–110. [DOI]
Rietkerk M, Dekker SC, de Ruiter PC, van de Koppel J. Self-organized patchiness and catastrophic shifts in ecosystems. Science. 2004;305:19269. [DOI] [PubMed]
Ostrom E. Sustainable Social-Ecological Systems: An Impossibility? SSRN J. 2007. [DOI]
Pomeroy RS. Community management and common property of coastal fisheries in Asia and the Pacific: concepts, methods and experiences. Proceedings of the Workshop on Community Management and Common Property of Coastal Fisheries and Upland Resources in Asia and the Pacific; 1993 Jun 21–23; Cavite, Philippines. Metro Manila: International Center for Living Aquatic Resources Management (ICLARM); 1994.
Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:165569. [DOI] [PubMed] [PMC]
Chen S, Saeed AFUH, Liu Q, Jiang Q, Xu H, Xiao GG, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther. 2023;8:207. [DOI] [PubMed] [PMC]
Wang Y, Zhao M, Liu S, Guo J, Lu Y, Cheng J, et al. Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases. Cell Death Dis. 2020;11:924. [DOI] [PubMed] [PMC]
Yang P, Zhou W, Li C, Zhang M, Jiang Y, Jiang R, et al. Kupffer-cell-expressed transmembrane TNF-α is a major contributor to lipopolysaccharide and D-galactosamine-induced liver injury. Cell Tissue Res. 2016;363:37183. [DOI] [PubMed]
Seki E, Minicis SD, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13:132432. [DOI] [PubMed]
Su GL, Klein RD, Aminlari A, Zhang HY, Steinstraesser L, Alarcon WH, et al. Kupffer cell activation by lipopolysaccharide in rats: role for lipopolysaccharide binding protein and toll-like receptor 4. Hepatology. 2000;31:9326. [DOI] [PubMed]
Burns T, Köster F, editors. Governing education in a complex world. In: Educational Research and Innovation.Paris: OECD Publishing; 2016. [DOI]
Guo Z, Wu Q, Xie P, Wang J, Lv W. Immunomodulation in non-alcoholic fatty liver disease: exploring mechanisms and applications. Front Immunol. 2024;15:1336493. [DOI] [PubMed] [PMC]
Hernández A, Reyes D, Geng Y, Arab JP, Cabrera D, Sepulveda R, et al. Extracellular vesicles derived from fat-laden hepatocytes undergoing chemical hypoxia promote a pro-fibrotic phenotype in hepatic stellate cells. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165857. [DOI] [PubMed]
Cheng Z, Chu H, Seki E, Lin R, Yang L. Hepatocyte programmed cell death: the trigger for inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis. Front Cell Dev Biol. 2024;12:1431921. [DOI] [PubMed] [PMC]
Koliou M, Lindt JWvd, McAllister TP, Ellingwood BR, Dillard M, Cutler H. State of the research in community resilience: progress and challenges. Sustain Resilient Infrastruct. 2018:10.1080/23789689.2017.1418547. [DOI] [PubMed] [PMC]
Anastasiou D, Ballis A, Guizani A, Kallandranis C, Lakhal F. Monetary policy impact on sustainability: Analyzing interest rates and corporate carbon emissions. J Environ Manage. 2024;368:122119. [DOI] [PubMed]
Dille M, Nikolic A, Wahlers N, Fahlbusch P, Jacob S, Hartwig S, et al. Long-term adjustment of hepatic lipid metabolism after chronic stress and the role of FGF21. Biochim Biophys Acta Mol Basis Dis. 2022;1868:166286. [DOI] [PubMed]
Dai Q, Ain Q, Seth N, Rooney M, Zipprich A. Liver sinusoidal endothelial cells: Friend or foe in metabolic dysfunction- associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Dig Liver Dis. 2025;57:493503. [DOI] [PubMed]
Fan Y, Zhang S, Wang Y, Wang H, Li H, Bai L. Inter-organ metabolic interaction networks in non-alcoholic fatty liver disease. Front Endocrinol (Lausanne). 2025;15:1494560. [DOI] [PubMed] [PMC]
Zhang X, Ji X, Wang Q, Li JZ. New insight into inter-organ crosstalk contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Protein Cell. 2018;9:16477. [DOI] [PubMed] [PMC]
Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol. 2023;21:71933. [DOI] [PubMed] [PMC]
Hao W, Cheng C, Cheng T. Addressing the alarming link between nonalcoholic fatty liver disease and cardiovascular mortality in men. World J Cardiol. 2024;16:5027. [DOI] [PubMed] [PMC]
Batta A, Hatwal J. Excess cardiovascular mortality in men with non-alcoholic fatty liver disease: A cause for concern! World J Cardiol. 2024;16:3804. [DOI] [PubMed] [PMC]
Arslan U, Yenerçağ M. Relationship between non-alcoholic fatty liver disease and coronary heart disease. World J Clin Cases. 2020;8:468899. [DOI] [PubMed] [PMC]
Basil B, Myke-Mbata BK, Eze OE, Akubue AU. From adiposity to steatosis: metabolic dysfunction-associated steatotic liver disease, a hepatic expression of metabolic syndrome - current insights and future directions. Clin Diabetes Endocrinol. 2024;10:39. [DOI] [PubMed] [PMC]
Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver Int. 2012;32:199213. [DOI] [PubMed] [PMC]
Schnabl B, Damman CJ, Carr RM. Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations. J Clin Invest. 2025;135:e186423. [DOI] [PubMed] [PMC]
Wang R, Tang R, Li B, Ma X, Schnabl B, Tilg H. Gut microbiome, liver immunology, and liver diseases. Cell Mol Immunol. 2021;18:417. [DOI] [PubMed] [PMC]
Anand N, Gorantla VR, Chidambaram SB. The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders. Cells. 2022;12:54. [DOI] [PubMed] [PMC]
An L, Wirth U, Koch D, Schirren M, Drefs M, Koliogiannis D, et al. The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases. J Gastrointest Surg. 2022;26:67183. [DOI] [PubMed] [PMC]
Vincenzo FD, Gaudio AD, Petito V, Lopetuso LR, Scaldaferri F. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Intern Emerg Med. 2024;19:27593. [DOI] [PubMed] [PMC]
Geng Y, Wang J, Serna-Salas SA, Villanueva AH, Buist-Homan M, Arrese M, et al. Hepatic stellate cells induce an inflammatory phenotype in Kupffer cells via the release of extracellular vesicles. J Cell Physiol. 2023;238:2293303. [DOI] [PubMed]
Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2024;9:97. [DOI] [PubMed] [PMC]
Stein J, Keuschnigg M, van de Rijt A. Network segregation and the propagation of misinformation. Sci Rep. 2023;13:917. [DOI] [PubMed] [PMC]
Kaufmann B, Seyfried N, Hartmann D, Hartmann P. Probiotics, prebiotics, and synbiotics in nonalcoholic fatty liver disease and alcohol-associated liver disease. Am J Physiol Gastrointest Liver Physiol. 2023;325:G4261. [DOI] [PubMed] [PMC]
Sun X, Shukla M, Wang W, Li S. Unlocking gut-liver-brain axis communication metabolites: energy metabolism, immunity and barriers. NPJ Biofilms Microbiomes. 2024;10:136. [DOI] [PubMed] [PMC]
Heindel JJ, Blumberg B, Cave M, Machtinger R, Mantovani A, Mendez MA, et al. Metabolism disrupting chemicals and metabolic disorders. Reprod Toxicol. 2017;68:333. [DOI] [PubMed] [PMC]
Prida E, Álvarez-Delgado S, Pérez-Lois R, Soto-Tielas M, Estany-Gestal A, Fernø J, et al. Liver Brain Interactions: Focus on FGF21 a Systematic Review. Int J Mol Sci. 2022;23:13318. [DOI] [PubMed] [PMC]
Kjærgaard K, Mikkelsen ACD, Landau AM, Eriksen PL, Hamilton-Dutoit S, Magnusson NE, et al. Cognitive dysfunction in early experimental metabolic dysfunction-associated steatotic liver disease is associated with systemic inflammation and neuroinflammation. JHEP Rep. 2023;6:100992. [DOI] [PubMed] [PMC]
Rad NK, Heydari Z, Tamimi AH, Zahmatkesh E, Shpichka A, Barekat M, et al. Review on Kidney-Liver Crosstalk: Pathophysiology of Their Disorders. Cell J. 2024;26:98111. [DOI] [PubMed] [PMC]
Sandireddy R, Sakthivel S, Gupta P, Behari J, Tripathi M, Singh BK. Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases. Front Cell Dev Biol. 2024;12:1433857. [DOI] [PubMed] [PMC]
Chancharoenthana W, Leelahavanichkul A. Acute kidney injury spectrum in patients with chronic liver disease: Where do we stand? World J Gastroenterol. 2019;25:3684703. [DOI] [PubMed] [PMC]
Sakers A, Siqueira MKD, Seale P, Villanueva CJ. Adipose-tissue plasticity in health and disease. Cell. 2022;185:41946. [DOI] [PubMed] [PMC]
Sarmento-Cabral A, Peinado JR, Halliday LC, Malagon MM, Castaño JP, Kineman RD, et al. Adipokines (Leptin, Adiponectin, Resistin) Differentially Regulate All Hormonal Cell Types in Primary Anterior Pituitary Cell Cultures from Two Primate Species. Sci Rep. 2017;7:43537. [DOI] [PubMed] [PMC]
Jain P, Jain A, Deshmukh R, Samal P, Satapathy T, Ajazuddin. Metabolic dysfunction-associated steatotic liver disease (MASLD): Exploring systemic impacts and innovative therapies. Clin Res Hepatol Gastroenterol. 2025;49:102584. [DOI] [PubMed]
Chen C, Xie L, Zhang M, Shama, Cheng KKY, Jia W. The interplay between the muscle and liver in the regulation of glucolipid metabolism. J Mol Cell Biol. 2024;15:mjad073. [DOI] [PubMed] [PMC]
Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, et al. Energy metabolism in health and diseases. Signal Transduct Target Ther. 2025;10:69. [DOI] [PubMed] [PMC]
Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L. Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease. J Am Med Dir Assoc. 2016;17:78996. [DOI] [PubMed]
Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4:17797. [DOI] [PubMed] [PMC]
Kumar R, Prakash SS, Priyadarshi RN, Anand U. Sarcopenia in Chronic Liver Disease: A Metabolic Perspective. J Clin Transl Hepatol. 2022;10:121322. [DOI] [PubMed] [PMC]
Merz KE, Thurmond DC. Role of Skeletal Muscle in Insulin Resistance and Glucose Uptake. Compr Physiol. 2020;10:785809. [DOI] [PubMed] [PMC]
Hilliard KL, Allen E, Traber KE, Yamamoto K, Stauffer NM, Wasserman GA, et al. The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia. Am J Respir Cell Mol Biol. 2015;53:37890. [DOI] [PubMed] [PMC]
Kholdani C, Fares WH, Mohsenin V. Pulmonary hypertension in obstructive sleep apnea: is it clinically significant? A critical analysis of the association and pathophysiology. Pulm Circ. 2015;5:2207. [DOI] [PubMed] [PMC]
Tang H, Lv F, Zhang P, Liu J, Mao J. The impact of obstructive sleep apnea on nonalcoholic fatty liver disease. Front Endocrinol (Lausanne). 2023;14:1254459. [DOI] [PubMed] [PMC]
Foglia B, Novo E, Protopapa F, Maggiora M, Bocca C, Cannito S, et al. Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis. Cells. 2021;10:1764. [DOI] [PubMed] [PMC]
Sundaram SS, Halbower A, Pan Z, Robbins K, Capocelli KE, Klawitter J, et al. Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease. J Hepatol. 2016;65:5609. [DOI] [PubMed] [PMC]
Szabo G, Momen-Heravi F. Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2017;14:45566. [DOI] [PubMed] [PMC]
Cheng W, Xu C, Su Y, Shen Y, Yang Q, Zhao Y, et al. Engineered Extracellular Vesicles: A potential treatment for regeneration. iScience. 2023;26:108282. [DOI] [PubMed] [PMC]
Roefs MT, Sluijter JPG, Vader P. Extracellular Vesicle-Associated Proteins in Tissue Repair. Trends Cell Biol. 2020;30:9901013. [DOI] [PubMed]
Wang J, Wu Z, Xia M, Salas SS, Ospina JA, Buist-Homan M, et al. Extracellular vesicles derived from liver sinusoidal endothelial cells inhibit the activation of hepatic stellate cells and Kupffer cells in vitro. Biochim Biophys Acta Mol Basis Dis. 2024;1870:167020. [DOI] [PubMed]
Jiang W, Zeng Q, Liu C, Wang Y, Wang S, Chen E, et al. Huc-MSCs-derived exosomes alleviate non-alcoholic steatohepatitis by regulating macrophages polarization through miR-24-3p/STING axis. Stem Cell Res Ther. 2025;16:74. [DOI] [PubMed] [PMC]
Wu Z, Xia M, Wang J, Aguilar MM, Buist-Homan M, Moshage H. Extracellular vesicles originating from steatotic hepatocytes promote hepatic stellate cell senescence via AKT/mTOR signaling. Cell Biochem Funct. 2024;42:e4077. [DOI] [PubMed]
Wang X, Peng Z. Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease. Front Pharmacol. 2021;12:655557. [DOI] [PubMed] [PMC]
Shetty S, Lalor PF, Adams DH. Liver sinusoidal endothelial cells - gatekeepers of hepatic immunity. Nat Rev Gastroenterol Hepatol. 2018;15:55567. [DOI] [PubMed] [PMC]
Kumar MA, Baba SK, Sadida HQ, Marzooqi SA, Jerobin J, Altemani FH, et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct Target Ther. 2024;9:27. [DOI] [PubMed] [PMC]
Zhang J, Qiu X, Lei Y, Chen H, Wu D, Wang T, et al. Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells. Exp Mol Med. 2025;57:584600. [DOI] [PubMed] [PMC]
Wu R, Fan X, Wang Y, Shen M, Zheng Y, Zhao S, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Liver Immunity and Therapy. Front Immunol. 2022;13:833878. [DOI] [PubMed] [PMC]
Siregar I, Zulkarnain. The Relationship between Conflict and Social Change in the Perspective of Expert Theory: A Literature Review. ijahs. 2022;2:0916. [DOI]
Kew D, John AW. Civil Society and Peace Negotiations: Confronting Exclusion. Int Negot. 2008;13:1136. [DOI]
Bongiovanni L, Andriessen A, Wauben MHM, Hoen ENMN, Bruin Ad. Extracellular Vesicles: Novel Opportunities to Understand and Detect Neoplastic Diseases. Vet Pathol. 2021;58:45371. [DOI] [PubMed] [PMC]
Chan W, Chuah K, Rajaram RB, Lim L, Ratnasingam J, Vethakkan SR. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A State-of-the-Art Review. J Obes Metab Syndr. 2023;32:197213. [DOI] [PubMed] [PMC]
Wang J, Zhao F, Brouwer LA, Buist-Homan M, Wolters JC, Moshage H, et al. Collagen-rich liver-derived extracellular matrix hydrogels augment survival and function of primary rat liver sinusoidal endothelial cells and hepatocytes. Int J Biol Macromol. 2024;278:134717. [DOI] [PubMed]
Naba A. Mechanisms of assembly and remodelling of the extracellular matrix. Nat Rev Mol Cell Biol. 2024;25:86585. [DOI] [PubMed] [PMC]
Lozoya OA, Wauthier E, Turner RA, Barbier C, Prestwich GD, Guilak F, et al. Regulation of hepatic stem/progenitor phenotype by microenvironment stiffness in hydrogel models of the human liver stem cell niche. Biomaterials. 2011;32:7389402. [DOI] [PubMed] [PMC]
Li W, Li P, Li N, Du Y, Lü S, Elad D, et al. Matrix stiffness and shear stresses modulate hepatocyte functions in a fibrotic liver sinusoidal model. Am J Physiol Gastrointest Liver Physiol. 2021;320:G27282. [DOI] [PubMed] [PMC]
Ali M, Payne SL. Biomaterial-based cell delivery strategies to promote liver regeneration. Biomater Res. 2021;25:5. [DOI] [PubMed] [PMC]
Bedossa P, Paradis V. Liver extracellular matrix in health and disease. J Pathol. 2003;200:50415. [DOI] [PubMed]
Ford AJ, Jain G, Rajagopalan P. Designing a fibrotic microenvironment to investigate changes in human liver sinusoidal endothelial cell function. Acta Biomater. 2015;24:2207. [DOI] [PubMed]
Juin A, Planus E, Guillemot F, Horakova P, Albiges-Rizo C, Génot E, et al. Extracellular matrix rigidity controls podosome induction in microvascular endothelial cells. Biol Cell. 2013;105:4657. [DOI] [PubMed]
Morgan M, Webster A, Padowski J, Morrison R, Flint C, Simmons-Potter K, et al. Guided transformations for communities facing social and ecological change. Ecol Soc. 2024;29:20. [DOI]
Zhang Y, Li L, Dong L, Cheng Y, Huang X, Xue B, et al. Hydrogel-Based Strategies for Liver Tissue Engineering. Chem Bio Eng. 2024;1:887915. [DOI] [PubMed] [PMC]
Bhatt SS, Kumar JK, Laya S, Thakur G, Nune M. Scaffold-mediated liver regeneration: A comprehensive exploration of current advances. J Tissue Eng. 2024;15:20417314241286092. [DOI] [PubMed] [PMC]
Boyer-Diaz Z, Aristu-Zabalza P, Andrés-Rozas M, Robert C, Ortega-Ribera M, Fernández-Iglesias A, et al. Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease. J Hepatol. 2021;74:118899. [DOI] [PubMed]
Tsai H, Li T, Huang C, Huang S, Liu R, Yang Y, et al. Beneficial Effects of the Peroxisome Proliferator-Activated Receptor α/γ Agonist Aleglitazar on Progressive Hepatic and Splanchnic Abnormalities in Cirrhotic Rats with Portal Hypertension. Am J Pathol. 2018;188:160824. [DOI] [PubMed]
Zhang F, Kong D, Chen L, Zhang X, Lian N, Zhu X, et al. Peroxisome proliferator-activated receptor-γ interrupts angiogenic signal transduction by transrepression of platelet-derived growth factor-β receptor in hepatic stellate cells. J Cell Sci. 2014;127:30514. [DOI] [PubMed]
Singh A, Sohal A, Batta A. GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists: Novel therapeutic agents for metabolic dysfunction-associated steatohepatitis. World J Gastroenterol. 2024;30:520511. [DOI] [PubMed] [PMC]
Soresi M, Giannitrapani L. Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease. World J Gastroenterol. 2024;30:35417. [DOI] [PubMed] [PMC]
Zhou D, Fan J. Drug treatment for metabolic dysfunction-associated steatotic liver disease: Progress and direction. Chin Med J (Engl). 2024;137:268796. [DOI] [PubMed] [PMC]
Keam SJ. Resmetirom: First Approval. Drugs. 2024;84:72935. [DOI] [PubMed]
Xie Z, Li Y, Cheng L, Huang Y, Rao W, Shi H, et al. Potential therapeutic strategies for MASH: from preclinical to clinical development. Life Metab. 2024;3:loae029. [DOI] [PubMed] [PMC]
Fan J, Xu X, Yang R, Nan Y, Wei L, Jia J, et al.; Chinese Society of Hepatology, Chinese Medical Association. Guideline for the Prevention and Treatment of Metabolic Dysfunction-associated Fatty Liver Disease (Version 2024). J Clin Transl Hepatol. 2024;12:95574. [DOI] [PubMed] [PMC]
European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81:492542. [DOI] [PubMed]
Gastaldelli A, Stefan N, Häring H. Liver-targeting drugs and their effect on blood glucose and hepatic lipids. Diabetologia. 2021;64:146179. [DOI] [PubMed] [PMC]
Wang K, Zhang Y, Wang G, Hao H, Wang H. FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid. Med Res Rev. 2024;44:56886. [DOI] [PubMed]
Adorini L, Trauner M. FXR agonists in NASH treatment. J Hepatol. 2023;79:131731. [DOI] [PubMed]
Cite this Article
Export Citation
Wang J, Lei J, Harmsen MC, Moshage H. From cooperation to collapse: systemic failure in liver disease through a sociological lens. Explor Dig Dis. 2025;4:100580. https://doi.org/10.37349/edd.2025.100580
Article Metrics

View: 46

Download: 7

Times Cited: 0