Obesity is a complex, multifactorial chronic disease characterized by excessive accumulation of adipose tissue, which places a significant burden on both individual health and public health systems worldwide. Obesity is traditionally defined as a body mass index (BMI) of ≥ 30 kg/m² [1]. However, this cut-off value, although useful for large-scale epidemiological studies, does not fully capture the multiple genetic, environmental, and behavioral factors that contribute to obesity [2]. Additionally, certain populations develop metabolic dysfunction at lower values of BMI and therefore, ethnicity-specific definitions of obesity apply [3]. Among the organ systems most affected by obesity is the liver, which plays a central role in metabolism, detoxification, immunology, and the regulation of systemic energy homeostasis [4]. Abnormalities in liver function, often associated with obesity, affect the pathobiology of all types of chronic liver disease (CLD), including viral hepatitis, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma (HCC) [5]. BMI, while a clinically utilizable metric, is neither the only one nor devoid of limitations (typically in athletes and in patients with states of fluid retention) [6]. The anatomic location where adipose tissue is positioned predicts metabolic dysfunction accurately and, accordingly, measurements of waist circumference (WC) are another clinically usable, sex- and ethnic-specific anthropometric measurement [7–9]. “Clinical obesity”, which defines a chronic, systemic illness characterized by impaired functions of tissues, organs, or the entire body owing to excess adiposity, is a major advancement.

The increasing incidence of obesity can be attributed to rapid urbanization, sedentary lifestyles, and a global shift towards diets high in calorie-dense foods rich in fats and sugars [10]. These factors, combined with genetic predisposition, underlie the rise of obesity in both economically developed nations and countries undergoing rapid economic transition, affecting life expectancy, quality of life, healthcare expenditure, and workforce productivity [11]. It is estimated that billions of dollars are spent annually on healthcare costs related to overweight and obesity, putting a strain on healthcare systems worldwide [12]. In this context, the understanding of how obesity affects liver health is critical, as obesity may often perturb those crucial metabolic and detoxification processes for which the liver is responsible. In terms of pathophysiological mechanisms, obesity contributes to liver dysfunction through several interconnected pathways [13], including the excess release of free fatty acids (FFAs) and pro-inflammatory cytokines into the bloodstream, resulting in escalated reactive oxygen species (ROS) formation within the mitochondrial respiratory chain [14, 15]. Over time, systemic and hepatic insulin resistance (IR) dysregulate hepatic glucose output and fatty acid uptake [13], resulting in hepatic steatosis, i.e., the accumulation of fat in hepatocytes. Although simple steatosis can be relatively benign in some individuals, others progress to more severe forms such as MASH, cardiac structural and functional changes, as well as muscular and renal complications [14]. In addition to MASLD, obesity also affects the pathobiology of chronic viral hepatitis and cirrhosis, enhancing the risks of HCC with profound clinical implications and an urgent need for improved public health strategies and targeted therapeutic interventions [16].

Obesity develops when prolonged energy intake exceeds energy expenditure, leading to adipose tissue expansion through both hypertrophy (enlargement of existing adipocytes) and hyperplasia (increased adipocyte number). Hypercaloric diets and sedentary lifestyle cause lipids to accumulate not only in subcutaneous fat depots but also in visceral fat, liver, muscle, and other ectopic sites [13]. These lipid reservoirs release FFAs and pro-inflammatory cytokines [e.g., tumor necrosis factor-alpha (TNF-α), IL-6] that provoke low-grade, subclinical chronic inflammation and IR in both adipose tissue and peripheral organs [14, 15]. IR, in turn, worsens ectopic fat deposition and perpetuates a cycle of metabolic dysfunction, ultimately disrupting hepatic, cardiovascular, and endocrine homeostasis.

Beyond the liver, obesity exhibits key comorbidities including type 2 diabetes mellitus (T2DM), arterial hypertension, dyslipidemia, and atherosclerosis, all of which substantially elevate the risk of cardiovascular disease (CVD) [9]. Furthermore, obesity is linked to chronic kidney disease, obstructive sleep apnea, osteoarthritis, certain cancers, and cognitive decline, underscoring the multifactorial burden of this condition.

Obesity affects over 1.9 billion people worldwide [17]. The burden of liver disease associated with obesity is compounded by overlapping risk factors such as metabolic syndrome (MetS), which includes central obesity, hyperglycemia, dyslipidemia, and hypertension, and is strongly associated with MASLD and MASH [18]. Additionally, the prevalence of obesity in high-income areas is inversely correlated with life expectancy in adults (Figure 1).

Moreover, the prevalence of adult overweight and obesity varies significantly between low- and high-income areas and can differ between males and females (Supplementary material). According to the regularly updated information provided by the World Obesity Observatory, which was last updated on April 8, 2025, the lowest incidence is currently found in Ethiopia (1%), while the highest incidence is found in American Samoa (80.2%). The growing clinical burden associated with obesity requires early detection, appropriate staging of liver disease, and careful consideration of interventions to prevent progression to cirrhosis or liver failure for individuals and their healthcare providers. Lifestyle modifications play a crucial role in improving clinical outcomes by reducing the number, activity, and composition of circulating pro-inflammatory blood cells [21]. In more advanced cases or in instances of morbid obesity, pharmacotherapy and bariatric surgery offer additional treatment options, although the evidence on their long-term impact on liver health is still evolving [22, 23]. Understanding the precise interplay between excess adipose tissue and liver function remains a challenge owing to heterogeneity of patient populations, variable genetic predisposition, and differences in environmental factors, which collectively hinder standardized treatment guidelines and targeted therapeutics [24]. Furthermore, there is still disagreement about the optimal diagnostic thresholds for MASLD and MASH, and screening guidelines [25]. As a result, clinicians often face uncertainty about the best possible approach to prevent or treat obesity-related liver disease in individual patients.

Here, we aim to provide a comprehensive understanding of the relationship between obesity and liver health, bridging the gap between general pathophysiological concepts and specific clinical implications. We seek to elucidate how obesity contributes to liver dysfunction and highlight the preventive, diagnostic, and management strategies that are most relevant to healthcare providers, researchers, and policy makers. By synthesizing the latest research findings and discussing future directions, we hope to provide guidance that can inform clinical decision making, promote effective patient counseling, and drive research into novel interventions. In addition, we explore the wider societal and economic burden of obesity-related liver disease, as understanding the cost-effectiveness of different intervention programs will be critical for policy makers seeking to contain costs while improving patient outcomes.

The review will discuss the pathophysiological interplay between adipose tissue, the gut microbiome, and the liver. We cover how obesity exacerbates alcohol-related liver damage and chronic viral hepatitis, underlining the ways in which excess adiposity can accelerate disease progression. We also highlight the negative impact of obesity on cirrhosis development and progression, as well as how it heightens the risk of HCC. By examining these intersections, we aim to shed light on how various forms of CLD converge in the context of obesity, thereby underscoring the broader clinical and societal significance of this epidemic. Our comprehensive approach spanning from epidemiology, clinical science, and pathobiology, together with an emphasis on liver damage in the context of obesity, render the present review article novel and different from similar published articles.

In preparing this review article, we conducted a comprehensive literature search using major scientific databases, including PubMed (https://pubmed.ncbi.nlm.nih.gov/), Scopus (https://www.scopus.com/home.uri), and Web of Science (https://www.webofknowledge.com/). We selected these databases because of their broad coverage of biomedical and clinical research, ensuring a thorough retrieval of relevant publications. The search terms used included various combinations of “obesity”, “liver”, “non-alcoholic fatty liver disease”, “metabolic dysfunction-associated steatotic liver”, “MASLD”, “metabolic dysfunction associated steatohepatitis”, “MASH”, “NAFLD”, “nonalcoholic steatohepatitis”, “NASH”, “metabolic syndrome”, and “steatosis,” using Boolean operators (AND, OR) to refine the results. We also reviewed relevant guidelines and position statements from professional societies such as the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), and other authoritative bodies. In addition to these database searches, our methodology included screening the reference lists of selected articles to identify further relevant studies that may not have been included in the initial search.

Articles were considered for inclusion if they focused on the conceptual links between obesity and liver disease, provided clinical data on diagnostic or therapeutic strategies, or offered novel insights into pathophysiological mechanisms. Priority was given to studies published within the last 10 years to ensure the timeliness of the review. However, seminal papers published earlier were also included if they addressed fundamental concepts that remain critical to current understanding. Studies involving pediatric populations were included where relevant, given the alarming rise in childhood obesity and its potential to catalyze early-onset liver disease. Following an initial screening of titles and abstracts, full-text articles were assessed for scientific quality, relevance to the aims of the review, and contribution to the understanding of the role of obesity in liver pathology. The methodological rigor of each study was assessed, including design [e.g., randomized controlled trial (RCT), cohort study, case-control study, or cross-sectional design], statistical power, and potential sources of bias. Finally, we synthesized the findings into key thematic categories that shape the structure of this review: (i) definitions and epidemiology, (ii) pathophysiology and mechanisms of disease, (iii) diagnostic approaches and disease assessment, (iv) clinical management strategies, and (v) future research directions and gaps.

The phenotypic heterogeneity of obesity poses a challenge in assessing cardiometabolic risk associated with a specific BMI [26]. Similar considerations may also apply to the risks of liver disease associated with different types of obesity. In the early 1950s, researchers discovered that the distribution of adipose tissue played a significant role in determining cardiometabolic risk [27]. This idea was further supported by the identification of subsets of patients who showed metabolic dysfunction despite having a lean phenotype, and conversely, individuals with obesity who appeared to be protected from metabolic dysfunction [27]. Imaging techniques have revolutionized the classification of obesity by enabling the quantitative assessment of the regional distribution of adipose tissue [26]. However, simple clinical observation, including measuring WC and other basic anthropometric indices, allows for the quick identification of android and gynoid patterns of obesity [28].

It is widely accepted that individuals with an excess of visceral adipose tissue (VAT), also known as android, central, truncal, visceral, or “apple type” obesity, have the highest probability of ectopic fat deposition and the most elevated cardiometabolic risk [26]. Conversely, subcutaneous obesity affecting the gluteo-femoral region, also known as gynoid or “pear type” obesity, is typically considered to be at low cardiometabolic risk [26]. The different cardiometabolic outcomes underlie variable attitudes of subcutaneous, visceral, and ectopic adipose tissue to store and release fatty acids and to synthesize and secrete adipokines [26]. Therefore, sex and reproductive status are major modifiers of the various obesity phenotypes [29].

Sarcopenic obesity is characterized by a bidirectional, pathogenic interaction between obesity and the loss of skeletal muscle mass and function. This ultimately leads to a synergistically increased cardiometabolic risk and functional impairment compared to the risks posed by each condition separately [30]. While these classifications remain clinically significant, other important factors influencing cardiometabolic risk include cardiorespiratory fitness (higher level is associated with lower accumulation of VAT), diet quality (poor diet increases cardiometabolic risk) and, in the context of precision medicine approaches, lifestyle habits should complement traditional anthropometric indices in the field of obesity, which should be referred to as ‘obesities’ [26].

Although there are various definitions of metabolic health [31], it is generally accepted that metabolically healthy obesity (MHO) is defined by a BMI of ≥ 30 kg/m² and a healthy metabolic status identified by the absence of components of the MetS [31, 32].

Approximately one in three individuals with obesity has MHO [32], and a continuous linear increasing trend in metabolically unhealthy obesity (MUO) has been reported among US adults from 1999 to 2018 [33]. Mechanistically, adult subjects with MHO present more brown adipose tissue (BAT) and higher thermogenesis than their metabolically unhealthy counterparts [34], suggesting that BAT presence and activity affect a healthier phenotype in subjects with overweight or obesity. Additionally, individuals with the MHO phenotype exhibit slightly increased bone turnover activity, probably as an initial skeletal compensatory response to the increased BMI [35].

Typically, MUO is considered a temporary and potentially evolving condition, situated between metabolically healthy lean individuals and MUO. Studies show that over half of individuals with MHO develop MUO within a 10-year period [32, 36]. Moreover, MHO is linked to a higher risk of cancer [37], CVD [38–40], chronic kidney disease [41], and depression, especially in women and individuals from North America and Europe, who may benefit from personalized interventions [42]. While the group of individuals with consistently stable MHO is a topic of great scientific interest, it is recommended to focus on weight management to prevent the transition from MHO to MUO status [32]. This is further discussed in Principles of treatment of obesity-associated CLD in this review.

The factors that determine a metabolically unhealthy phenotype among individuals with obesity are of significant scientific interest. Experimental evidence suggests that pro-inflammatory macrophages, the most common immune cells in adipose tissues, may act as a switch from MHO to MUO in a mouse model [36].

The orexigenic neuropeptide Y (NPY) plays a major role in humans, as exceeding the critical threshold of 471.5 pg/mL leads to an 18% increased risk of MUO for each 10 pg/mL increment in NPY serum levels, independently of confounding factors [43]. This study provides a compelling framework for other studies that document how sex, cultural achievements, lifestyle habits and exogenous factors (such as diet quality, sedentary behavior, smoking, alcohol, and drugs) impact intestinal dysbiosis, levels of general or visceral obesity, and contribute to an increased risk of MUO [44].

A large study involving 3,351,989 people identified a significant association between the transition from MHO to MUO and general characteristics, health behaviors, and metabolic components [45]. Male participants had a 1.30 times higher risk of progressing to MUO compared to females, and individuals in the lowest economic status were also at risk for this transition [odds ratio (OR): 1.08; 95% confidence interval (CI): 1.05 to 1.1]. Smoking, consuming more than 30 g of alcohol, and lack of regular exercise were also associated with this transition [45, 46].

In humans, higher adherence to unhealthier dietary patterns (i.e., consuming refined and processed foods) is associated with a reduced probability of having a healthy metabolic phenotype, while the opposite was observed for healthier dietary patterns [47]. Consistently, a one-unit increase in macronutrient quality index is associated with a 5% lower incident MUO (HR = 0.95; 95% CI: 0.92 to 0.99) [48]. In addition to a poor diet, the use of proton pump inhibitors may cause gut dysbiosis, which may predispose to MUO through a “leaky gut”, systemic low-grade inflammation, and reduced amounts of short-chain fatty acids such as butyrate that promote metabolic health [49]. Obesity, in its turn, is also a driver of gut dysbiosis [50], giving rise to a cause-and-effect vicious circle. A study from Korea analyzing data in 5,191 adults with obesity (BMI ≥ 25 kg/m²) found that food insecurity, older age, higher BMI, lower educational level, and lower physical activity were associated with MUO [51].

BMI-associated hyperuricemia is a risk factor for MUO compared to MHO in Chinese adults [52]. Advanced age and higher WC are significantly correlated with all metabolically unhealthy states [53], and both general and central obesity are associated with the risk of transitioning from MHO to MUO in a study conducted among women in Iran [54]. Regardless of underlying risk factors, transitioning from a metabolically healthy state to MUO is associated with higher risks of CVD and mortality [55, 56] and mortality owing to cancer [57].

Men and women store excess triglycerides differently, both in the adipose tissue and in ectopic sites (such as the liver and skeletal muscle). This is due to sex-specific differences in messenger RNA expression, protein content, and enzyme activities of skeletal muscle and hepatic lipid metabolic pathways [58]. As a result, MASLD is more prevalent in men than in women. Women tend to store more intramyocellular lipids (IMCL) than men, yet their risk of T2DM is not greater. During exercise, women rely more on lipid metabolism than men do, due to upregulated pathways of lipid oxidization [58]. Additionally, android fat predisposes individuals to MASLD, while gynoid fat protects against MASLD [59].

MUO is strongly associated with MASLD and the progressive variant of MASLD, MASH. A study from Iran involving 8,360 adults found that the risk of MASLD in individuals with the MHO phenotype increased by 8.92 times (95% CI: 2.20 to 15.30), and those with the MUO phenotype increased by 32.97 times (95% CI: 15.70 to 69.22) compared to the metabolically healthy-non-obese phenotype [60]. Another study conducted in Germany on 141 patients undergoing bariatric surgery found that, among the components of the pathophysiology of MUO, glucose metabolism predicts MASH more accurately than parameters of lipid metabolism, inflammation or the presence of CVD [61] indicating that IR is the main driver of progressive liver disease in these MUO subjects. Analysis of the liver biopsy database of the NASH Clinical Research Network has shown that low relative muscle mass independently predicted MASH in males (OR: 0.550; 95% CI: 0.312 to 0.970), while a high android to gynoid ratio was the independent risk factor for NASH in females (OR: 1.694; 95% CI: 1.073 to 2.674) [62]. Collectively, the data support a major role for body fat distribution and sarcopenic obesity in the development and progression of MASLD.

ALD defines a spectrum spanning from alcohol-associated steatosis, steatohepatitis, cirrhosis, and alcohol-associated HCC [63]. While typically occurring among those with cirrhosis, alcohol-associated hepatitis may occur at any stage of the spectrum [64]. The finding that not all those chronically exposed to hepatotoxic amounts of alcohol will develop progressive liver disease is a clue to co-factors modulating the risk of ALD.

A retrospective cohort study [65] classified 18,506 CLD-free at enrollment participants in the Mayo Clinic Biobank by self-reported alcohol consumption as: nondrinkers, moderate drinkers (0 to 2 drinks per day), and heavy drinkers (> 2 drinks per day). After a median 5.8 year follow-up among moderate drinkers, the risk of developing hepatic steatosis was high in patients with obesity [adjusted hazard ratio (AHR): 1.31; 95% CI: 1.03 to 1.67], insignificant in the overweight group (AHR: 0.86; 95% CI: 0.58 to 1.26), and decreased in the normal-BMI group (AHR: 0.48; 95% CI: 0.26 to 0.90). Heavy drinkers had an increased risk of hepatic steatosis irrespective of BMI. These data suggest that even moderate alcohol use is associated with the development of hepatic steatosis among individuals with obesity [65].

A prospective cohort study analyzing 414,209 participants from the UK Biobank study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with an increased risk of cirrhosis, HCC, and liver disease-related death in the general population [66]. This study suggests that the genetic background is another cofactor associated in the dangerous association linking obesity with progressive ALD. Further studies are needed to examine the factors responsible for ALD in obese individuals, to establish the basis for precision medicine strategies in this area.

The association of obesity with what is now known as MASLD and MASH dates back to 1867 and 1980, thanks to studies by Flint and Ludwig, respectively [88]. Unhealthy lifestyle habits that contribute to the development of obesity also play a major role in MASLD and MASH by enhancing intrahepatic de novo lipogenesis (DNL), extrahepatic and hepatic IR, dysfunctional gut-liver axis, and metabolic inflammation (metaflammation) [89]. Excess visceral fat leads to an overflow of FFAs to the liver, triggering a harmful cascade including oxidative stress (OS), endoplasmic reticulum (ER) stress, activation of protein kinase C (PKC) pathways, inflammation, excessive intrahepatic steatogenesis, progressive hepatocellular damage, and fibrosing MASH, as discussed in Pathobiology of liver damage in the obese of this article.

A meta-analysis of 21 cohort studies, including 13 prospective and 8 retrospective studies, totaling 381,655 participants, revealed an independent association between obesity and a 3.5-fold increased risk of developing MASLD compared to individuals with normal weight [relative risk (RR) = 3.53, 95% CI: 2.48 to 5.03, P < 0.001]. There was a clear dose-dependent relationship between BMI and MASLD risk with a relative risk of 1.20 per 1-unit increment in BMI (95% CI: 1.14 to 1.26, P < 0.001) [90]. It is essential to note that VAT, being close to the liver, is a significant risk factor for MASLD, even in lean MASLD subjects. Its levels increase in parallel with the stages of liver fibrosis and are closely linked to IR in the liver, muscle, and adipose tissue. This increase in VAT leads to heightened lipolysis and decreased levels of the insulin-sensitizing, anti-steatotic, and anti-inflammatory adipokine adiponectin [91]. These findings help to explain why obesity predicts a worse long-term prognosis in MASLD [92].

More than a quarter of a century ago, Brolin and colleagues [93] reported on 125 individuals with obesity in whom unsuspected cirrhosis was detected during gastric bariatric operations. These authors estimated that cirrhosis may have been caused by severe obesity in 74% of their patients. Although a proportion of these individuals might have had CLD owing to competing etiologies, we know that, in the context of the contemporary epidemic of obesity, these individuals might have progressed from MASLD to fibrosing MASH [94]. Of concern, obesity adversely impacts the natural course of cirrhosis by predisposing to white adipose tissue dysfunction, IR, and portal hypertension through incompletely characterized pathomechanisms [95].

Clinically, patients usually exhibit sarcopenic obesity, which determines higher rates of metabolic and physical dysfunction than either condition alone [96]. The diagnostic criteria for sarcopenic obesity in patients with cirrhosis are scarcely defined, and the most accurate diagnostic tool, cross-sectional imaging, has practical limitations for routine use in clinical practice [96]. Therapeutic approaches aim at improving nutrition, muscular mass, and strength [96, 97].

Future directions in this field comprise consensus definitions for sarcopenia, obesity, and sarcopenic obesity, an improved understanding of the complex pathogenesis of the muscle-liver-adipose tissue axis in cirrhosis [98], and evidence-based management recommendations for nutrition, exercise, and drug treatment [96].

In 2004, El-Serag [99] released the first epidemiological alert, indicating that 15% to 50% of HCC cases lacked evidence of viral or alcoholic risk factors. They also highlighted the emerging risk factor of the MetS for HCC in the USA. Recent epidemiological studies further support the idea that obesity may increase the risk of HCC, with clearer evidence for ALD and more limited evidence for CLD due to HBV, HCV, and MASLD [100]. However, in clinical practice, it is often challenging to separate obesity from more complex metabolic dysfunction. Over the last few decades, CLD due to viral causes, which was previously the most common risk factor for HCC in developing countries, has decreased. This decline has coincided with an increase in MASLD, making HCC relatively more common in Western countries [101]. Sex differences in HCC associated with MASLD and non-MASLD CLD have been discussed in previous studies [102, 103]. Metabolic comorbidities are significant risk factors for HCC and cholangiocarcinoma, the second most common type of primary liver cancer, through various pathomechanisms that have been reviewed elsewhere [101].

Below, we will highlight ALD, chronic viral hepatitis, and hepatic carcinogenesis to illustrate how obesity amplifies pathogenic pathways across a spectrum of distinct hepatic insults. This occurs through metabolic and inflammatory pathways, hastening the progression toward advanced liver disease.

Excess body weight and the accumulation of adipose tissue contribute to the development of MASLD, which begins with simple steatosis and can eventually progress to MASH, fibrosis, cirrhosis, and ultimately HCC in some individuals [16] (Figure 2). The following sections will detail how obesity promotes liver damage through IR, lipotoxicity, systemic inflammation, OS, and alterations in the gut-liver axis, leading to significant and potentially irreversible liver injury.

In obesity, elevated levels of FFAs and pro-inflammatory cytokines can interfere with insulin signaling pathways, impairing the ability of insulin to adequately regulate blood glucose levels and suppress hepatic glucose output, leading to metabolic dysfunction [112]. This state of IR has profound effects on glucose and lipid homeostasis. As peripheral tissues, such as adipocytes, become increasingly resistant to the effects of insulin, they release more FFAs into circulation. The liver is then exposed to these circulating FFAs, which are taken up by hepatocytes via plasma-membrane-associated proteins and are either oxidized or stored as triglycerides within the liver [113]. With prolonged excess supply, the hepatic lipid storage capacity of the liver can become overwhelmed and maladaptive, leading to steatosis, which lays the groundwork for potential progression to steatohepatitis and ultimately more advanced liver disease.

Steatosis initiates a series of cellular stress responses collectively known as lipotoxicity. Various forms of lipids, particularly certain FFAs and their derivatives (e.g., diacylglycerols, ceramides), can be toxic to hepatocytes and induce lipid-induced hepatic IR [114]. When hepatic lipid species accumulate, they impair mitochondrial function, disrupt ER homeostasis, and generate ROS [115]. Excessive fatty acid load can overwhelm and damage mitochondria, leading to abundant ROS production that further compromises mitochondrial integrity and causes oxidative damage to cellular lipids, proteins, and DNA [115]. Additionally, ER stress can trigger the unfolded protein response (UPR), which aims to restore proper protein folding. If the UPR fails to relieve ER stress, it can result in hepatocyte apoptosis or necrosis. Therefore, in obesity, lipid overload and lipotoxicity generate a cycle of progressive liver damage.

A key feature of obesity is the presence of chronic low-grade inflammation. Adipose tissue, particularly VAT, serves not only as a passive energy storage depot but also as an active endocrine organ that secretes numerous hormones and cytokines, such as TNF-α, interleukins (e.g., IL-6, IL-1β), and adipokines (e.g., leptin, adiponectin). In obesity, the balance of these secreted factors may shift towards a pro-inflammatory profile, further worsening IR and promoting local and systemic inflammation. Within the liver, KCs, which are resident macrophages, play a crucial role in orchestrating the inflammatory response [116]. Under normal conditions, KCs help clear pathogens and cellular debris, maintain tissue homeostasis, and limit tissue injury [117, 118]. However, in obesity, exposure to elevated levels of fatty acids, endotoxins, and inflammatory mediators activates KCs, leading to the production of various cytokines, including TNF-α, IL-1β, and IL-6, which perpetuate inflammatory signaling within the liver [116]. This increased inflammatory environment attracts circulating monocytes and other immune cells, contributing to a continuous inflammatory cycle. Over time, persistent inflammation triggers fibrogenic responses, paving the way for more advanced liver damage [119].

The progression from simple steatosis to MASH may be accompanied by liver fibrosis, primarily driven by hepatic stellate cells (HSCs). Normally quiescent in the space of Disse, they store vitamin A and other retinoids [120]. However, when exposed to inflammatory mediators, ROS, and signals from injured hepatocytes, HSCs transform into activated myofibroblast-like cells. This activation is characterized by a significant increase in extracellular matrix (ECM) production, including collagens I and III, loss of normal stellate cell functions [121], and secretion of pro-inflammatory and pro-fibrotic cytokines. In advanced disease stages, excessive ECM deposition distorts liver architecture and leads to cirrhosis, which gradually reduces liver function and can result in portal hypertension, variceal bleeding, liver failure, and increased risk of HCC. Due to their crucial role in fibrogenesis, HSCs have become a focal target of anti-fibrotic therapies [121].

OS plays a central role in obesity-related CLD [122]. When the capacity of mitochondria for effective oxidative phosphorylation is exceeded or partially reduced, ROS accumulate [14, 15]. These ROS, such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, are highly reactive molecules that can damage cellular structures. In addition to mitochondria, other sources of ROS include peroxisomal and microsomal oxidation of FAs, as well as activated immune cells in the liver. Some of the main downstream consequences of elevated ROS levels in hepatocytes include (i) lipid peroxidation—ROS attack polyunsaturated fatty acids in cell membranes, producing breakdown products that further propagate oxidative damage, (ii) protein oxidation—oxidative changes to proteins can impede their function and lead to their degradation, affecting structural proteins and enzymes crucial for cellular functionality, (iii) DNA damage—ROS can cause mutations and strand breaks in DNA, contributing to genomic instability that could increase the risk of malignant transformation, (iv) OS also interacts with inflammatory pathways, promoting the activation of NF-κB and other transcription factors that increase the production of cytokines and promote carcinogenesis [123]. Therefore, oxidative damage directly harms hepatocytes and contributes to fueling harmful cycle of inflammation and cellular stress.

Adipose tissue secretes a complex array of liver-impacting adipokines, including leptin, adiponectin, resistin, visfatin, and others [124]. In obesity, the profile of these adipokines can be altered in ways that promote both metabolic dysregulation and inflammation.

Leptin levels, which physiologically regulate appetite and energy expenditure, tend to rise in obesity due to leptin resistance. High levels of leptin can stimulate KCs, which further drive the production of pro-inflammatory mediators and directly influence HSCs to promote fibrosis [125]. Serdyukov and colleagues [126], based on analysis of young and middle-aged men, have proposed the definition of “metabolically neutral obesity” based on the presence of MHO and leptinemia < 3.5 ng/mL. These men with “metabolically neutral obesity” had a low prevalence of dyslipidemia, prediabetes, and carotid atherosclerosis compared to MHO subjects. However, no details have been published regarding liver health in these subjects, and additional studies comprising female subjects, older individuals, and longitudinal hard cardiometabolic outcomes are expected.

Adiponectin, which normally activates glucose transport and FFA oxidation and downregulates inflammation through the PPARγ pathway, is typically reduced in obesity [127]. Adiponectin exerts insulin-sensitizing, anti-inflammatory, and anti-fibrotic effects, in part by improving FA oxidation in hepatocytes and attenuating the production of pro-inflammatory cytokines [128]. Reduced adiponectin levels in obesity thus remove an important protective mechanism against liver injury. The imbalance in these and other adipokines highlights the complex endocrine crosstalk between adipose tissue and the liver in driving the pathogenesis of MASLD.

Accumulating evidence emphasizes the importance of the gut-liver axis in the pathobiology of obesity-related liver damage [129]. The gut microbiota, consisting of trillions of microorganisms, plays a central role in metabolism, bile acid turnover, and immunity [129]. In obesity, dysbiosis can lead to an increased permeability of the intestinal barrier, often referred to as “leaky gut”, allowing bacterial endotoxins, particularly lipopolysaccharides (LPS), to translocate from the intestinal lumen into the portal circulation [130]. These endotoxins stimulate KCs and other immune cells in the liver to secrete pro-inflammatory cytokines, worsening liver inflammation and IR [131]. Additionally, changes in bile acid profiles modulated by gut bacteria can also impact metabolic processes in the liver, further exacerbating steatosis and inflammation [129].

The ER is responsible for the proper folding and processing of proteins before their transport to other cellular compartments or to the extracellular space [132]. When hepatocytes are exposed to nutrient overload, pro-inflammatory signals, and toxic lipid metabolites, the protein-folding capacity of the ER can be overwhelmed, leading to an accumulation of misfolded or unfolded proteins [133]. This activates an adaptive program known as the UPR aimed at restoring homeostasis by reducing protein translation, promoting proper protein folding by up-regulating chaperones, and enhancing protein degradation pathways [132, 133]. If these compensatory mechanisms fail, the cell may activate apoptotic pathways, leading to hepatocyte cell death. Chronic ER stress and subsequent apoptosis contribute to ongoing liver injury and inflammation, perpetuating MASLD and MASH. Importantly, signaling molecules such as C/EBP homologous protein (CHOP) and JNK (c-Jun N-terminal kinase) have been implicated in ER stress-induced apoptosis, providing potential molecular targets for therapeutic intervention [134].

Polymorphisms in genes involved in lipid metabolism, insulin signaling, and inflammatory pathways may increase the risk of MASLD and accelerate its progression to fibrosis. For example, variants in the patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acetyltransferase domain-containing protein 7 (MBOAT7) genes have been strongly associated with MASLD and MASH by affecting triglyceride packaging and export, hepatic VLDL secretion, and predisposing to more severe disease phenotypes. In addition, epigenetic modifications can alter gene expression patterns influenced by various environmental factors [135–137]. This complex interplay of genetics and environment may account for the large inter-individual disease variability and heterogeneity, underscoring the importance of personalized approaches to prevention and treatment.

Although many obese individuals with MASLD remain stable or have only mild liver disease, a proportion may progress to MASH, cirrhosis, end-stage liver failure, and MASH-HCC [138, 139]. Therefore, early identification and monitoring of MASH patients at high risk of cirrhosis and HCC are of paramount importance.

As discussed in Principles of treatment of obesity-associated CLD, lifestyle interventions remain the initial cornerstone of therapy for MASLD and MASH [140]. However, adherence to long-term lifestyle changes can be challenging for many individuals. Novel agents targeting specific pathogenic mechanisms, such as IR, de novo lipogenesis, and fibrogenesis, are currently under investigation. These drugs modify bile acid signaling (e.g., obeticholic acid), reduce lipotoxic intermediates (e.g., acetyl-CoA carboxylase inhibitors), activate the thyroid hormone receptor, or target inflammatory cascades (e.g., IL-1β or TNF-α inhibitors), representing promising avenues for the treatment of MASLD/MASH (Table 3) [119, 141–156].

Moreover, the emerging focus on the gut-liver axis has prompted research into probiotics, prebiotics, and drugs aimed at restoring a healthy microbiome [157]. In selected cases, bariatric surgery may be considered to reduce body weight and improve liver histology [22]. However, larger-scale studies are needed to elucidate the long-term effects of these interventions on cirrhosis and complications such as HCC. In addition to refining therapeutic modalities, further research into genetic and epigenetic factors will be crucial for risk stratification and personalized treatment approaches. As the prevalence of obesity continues to rise, effective disease prevention, diagnosis, and management strategies are becoming increasingly urgent for healthcare systems worldwide.

Moving forward, a comprehensive research agenda should prioritize:

Development of precise phenotyping strategies incorporating metabolic markers, imaging technologies, and genomics to accurately classify obesity subtypes.

For the implementation of these goals, several activities are required that must be addressed by patients, clinicians, researchers, and food companies (Table 4). Implementing these priorities will refine the classification of obesity, clarify the role of the gut-liver axis in disease progression, and support the safe long-term application of emerging therapies and surgical approaches. In parallel, patient education, cost-effective treatment models, and public health policies that address socio-economic determinants will foster more effective and equitable strategies for obesity prevention and care worldwide.

Fecal microbiota transplantation (FMT) involves transferring fecal matter from a donor into the intestinal tract of a recipient with the aim of modifying the recipient’s gut microbiota to provide health benefits [172]. A systematic review and meta-analysis of studies on individuals with obesity and related metabolic issues demonstrated significant improvements in body weight (WMD = –4.77, 95% CI: –7.40 to –2.14), BMI values (WMD = –1.59, 95% CI: –2.21 to –0.97), HOMA-IR (WMD = –0.79, 95% CI: –1.57 to –0.00), and HbA1c (WMD = –0.65, 95% CI: –0.75 to –0.55) after FMT treatment compared to pre-FMT baseline values [173]. The success of FMT depends on the microbial diversity and composition of the donor feces [174], underscoring the necessity for further research to identify the characteristics of an ideal donor.

Confronted with the often-disappointing results of lifestyle changes alone, pharmacological treatment of obesity remains one of the key options. Recent advances have revolutionized present treatment schedules and promise even more substantial innovations soon [176]. According to guidelines, those eligible for drug treatment of obesity are subjects who still have a BMI ≥ 30 kg/m² (or ≥ 27 kg/m² with an obesity-related comorbidity) despite attempting lifestyle changes [177]. While analysis of rare obesity syndromes with metreleptin and setmelanotide is beyond the scope of this review, the principal drugs approved for chronic use in non-syndromic obesity are orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide [177].

Semaglutide is one of the most studied and widely used anti-obesity medications. It is available as a weekly subcutaneous injection or a daily oral medication and has been shown to effectively promote an average weight loss of 11.62 kg and reduce WC by up to 9.4 cm compared to placebo [178]. In addition, semaglutide has been found to reduce blood pressure, fasting blood glucose, C-reactive protein, and improve lipid profiles, offering cardiovascular benefits to patients with established atherosclerotic CVD. It also reduces the risk of renal outcomes and cardiovascular-related mortality and may improve metabolic dysfunction in some patients [178]. The use of semaglutide has been associated with improved mental health and quality of life. However, weight regain often occurs after discontinuing semaglutide, necessitating long-term maintenance strategies [178]. Some potential side effects of semaglutide include mild-to-moderate gastrointestinal complaints and the risk of hypoglycemia [178].

Traditionally, certain endoscopic techniques, such as intragastric balloon (IGB), have been considered as a bridge to bariatric surgery for individuals at high surgical risk. Interestingly, a recent meta-analysis of 19 published studies totaling 911 patients has shown that IGB may play an important role in addressing the treatment gap in NAFLD management. This is achieved by improving not only body weight, BMI, glycated hemoglobin and HOMA-IR but also histological parameters including NAFLD activity score (NAS): MD: –3.0 (95% CI: –2.41 to –3.59), ALT: MD: –10.40 U/L (95% CI: –7.31 to –13.49), liver volume: MD: –397.9 (95% CI: –212.78 to 1,008.58), and liver steatosis: MD: –37.76 dB/m (95% CI: –21.59 to –53.92) [183].

More recently, endoscopic duodenal mucosa hydrothermal ablation of the superficial duodenal mucosal layers, followed by resurfacing of the mucosal interface, shows promise in resetting and correcting any abnormal signaling from the duodenal mucosa. This procedure eventually results in improved pancreatic endocrine function and glucose tolerance due to restored normal mucosal surface [184]. The procedure is safe and well-tolerated and has demonstrated metabolic benefits and reduced LFC primarily in diabetic patients. Its effectiveness in non-diabetic obesity remains under evaluation.

Adults with a BMI ≥ 40 kg/m² (or ≥ 35 with obesity-related comorbidities) are candidates for bariatric and metabolic surgery [185]. These surgeries restrict food intake, reduce nutrient absorption, or alter gut hormones to achieve weight loss and improve metabolic health through surgical manipulation of the proximal GI tract [186].

A meta-analytic review of thirty published studies totaling 3,134 patients has shown that bariatric surgery significantly reduced BMI (ratio of means, 0.79), induced a 72% reduction of LFC (assessed with MRI-PDFF) a reduction of NAS by 60% at 3–6 months and by 50% at 36–60 months; a reduction of the fraction of patients with steatosis; a decrease of lobular inflammation, ballooning degeneration and significant fibrosis (≥ F2) [187]. Of interest, Roux-en-Y gastric bypass induces the reversal of metabolic dysfunction among individuals with MUO [188].

Finally, a somewhat neglected topic of great clinical and scientific significance is the outcome of cirrhotic individuals with portal hypertension and severe obesity [189]. Additional studies are therefore required to provide evidence-based recommendations.