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 [30–32].

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].

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].

LSECs play a central role in maintaining metabolic homeostasis by regulating nutrient and oxygen exchange, as well as preventing excessive immune activation [26, 46–48]. 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 [52–55]. Without intervention, this process escalates, further destabilizing the hepatic microenvironment [55].

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].

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, 65–67].

Chronic KC activation propagates hepatocyte injury and exacerbates fibrosis by stimulating HSC activation [67–69]. 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].

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 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.

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 [81–85]. 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.

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.

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.

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 [99–101]. 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.

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.

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.

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.

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]:

1)

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

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].

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 [131–133]. By providing a structural and biochemical niche, ECM hydrogels may:

1)

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

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].

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 [142–144]. 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, 149–151]. 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].

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.

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.