Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Mechanisms, Clinical Implications and Therapeutic Advances

Abstract

Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide, affecting ~25%-30% of the adult population, with higher prevalence observed in individuals with obesity and type 2 diabetes. Among reported MASLD cases, prevalence is consistently higher in men than in women, and global incidence has risen by ~50% over the past two decades, mirroring the global rise in obesity and metabolic syndrome. MASLD encompasses a spectrum of hepatic pathologies ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Despite its high prevalence, the heterogeneity in disease progression and relative absence of approved pharmacological therapies pose challenges for effective clinical management.

Methods and results: This review synthesises current literature on MASLD across epidemiology, pathophysiology, clinical presentation and treatment. Key molecular mechanisms, including lipid metabolism dysregulation, insulin resistance and mitochondrial dysfunction, are examined with a focus on understanding the basis for progression to metabolic dysfunction-associated steatohepatitis (MASH). Clinical manifestations, diagnostic tools and risk stratification systems for MASLD are summarised. Current and emerging therapies such as lifestyle interventions, pharmacological agents and microbiome-targeted strategies are reviewed. The review also highlights ongoing challenges, including diagnostic limitations, disease heterogeneity and disparities in care.

Conclusion: MASLD is a complex, multifactorial liver disease with a growing public health impact, driven by the rising prevalence of metabolic syndrome. Mitochondrial dysfunction is a critical nexus linking genetic susceptibility to metabolic stress and inflammatory responses. Preclinical models that capture these mitochondrial contributions are vital for therapeutic discovery and for advancing personalised medicine approaches in MASLD care.

Keywords: Western‐style diet; mitochondrial dysfunction‐associated steatohepatitis (MASH); mitochondrial dysfunction‐associated steatotic liver disease (MASLD); mitochondrial genetics.

FIGURE 1

Diverse liver cell types cooperatively drive health and contribute to MASLD pathogenesis. (A) In healthy liver tissue, distinct parenchymal (hepatocytes) and non‐parenchymal (Kupffer, hepatic stellate, liver sinusoidal endothelial and cholangiocytes) cell types coordinate essential functions, including energy metabolism, detoxification, immune surveillance and protein and bile acid synthesis. (B) During MASLD progression, all major liver cell types undergo pathological changes. Hepatocytes accumulate fat and become inflamed and injured. Kupffer cells and hepatic stellate cells are activated, promoting inflammation and fibrosis through cytokine secretion and extracellular matrix deposition. Liver sinusoidal endothelial cells lose their fenestrations (capillarisation) and develop basement membranes, impairing nutrient and oxygen exchange. Cholangiocytes expand and remodel, contributing to ductular reactions and disease progression.

FIGURE 2

Transition from NAFLD/NASH to MASLD/MASH nomenclature. Updated terminology for fatty liver disease, reflecting the shift from exclusion‐based definitions (NAFLD and NASH) to a framework grounded in metabolic dysfunction (MASLD and MASH).

FIGURE 3

Global distribution of MASLD cases, burden and trends in prevalence. Geographic patterns in metabolic dysfunction‐associated steatotic liver disease (MASLD) epidemic. Countries in red represent regions with the highest current prevalence burden, notably in East Asia, South Asia and Middle East/North Africa. Regions in orange, including much of Western Europe, demonstrate the fastest relative increase in MASLD cases since 1990. Areas in yellow, primarily in sub‐Saharan Africa and Latin America have experienced a steep rise in recent years, driven by urbanisation, dietary shifts and decreased physical activity.

FIGURE 4

Progression of metabolic‐dysfunction steatotic liver disease (MASLD). Natural progression of MASLD, beginning with a benign healthy liver and progressing through the reversible stages of lipogenesis resulting in metabolic dysfunction‐associated steatotic liver (MASL), and inflammation leading to metabolic dysfunction‐associated steatohepatitis (MASH). Then the beginning of the irreversible stages, starting with fibrosis, cirrhosis and ultimately hepatocellular carcinoma (HCC). This continuum highlights the escalating severity of liver damage driven by metabolic dysfunction and underscores the urgency of early detection and intervention.

FIGURE 5

The interplay of mitochondrial fragmentation, impaired mitophagy, oxidative stress and apoptosis in MASLD. The interconnected pathways contributing to mitochondrial dysfunction in Metabolic Dysfunction‐Associated Steatotic Liver Disease (MASLD). Disrupted mitochondrial dynamics, particularly excessive fragmentation and impaired fusion, impair energy metabolism and promote oxidative stress. Impaired mitophagy leads to the accumulation of dysfunctional mitochondria, further exacerbating inflammation and fibrosis. Impaired lipid oxidation and oxidative phosphorylation (OXPHOS) increase reactive oxygen species (ROS) and decrease energy production. These changes promote oxidative stress, mitochondrial damage and hepatocyte injury, while also activating hepatic stellate cells, which contribute to fibrogenesis and amplify hepatic inflammation. Mitochondrial calcium (Ca²⁺) overload triggers additional ROS production and opening of the mitochondrial permeability transition pore, resulting in hepatocyte death, loss of membrane potential and cytochrome c release.

FIGURE 6

Interplay between peripheral and hepatic insulin resistance in MASLD pathogenesis. Peripheral insulin resistance increases circulation free fatty acids and hyperinsulinemia, which in turn drive hepatic insulin resistance, gluconeogenesis and lipogenesis. These processes promote steatosis, mitochondrial dysfunction and progression from MASLD to MASH.

FIGURE 7

The multiple parallel‐hit hypothesis explains the progression of metabolic dysfunction‐ associated steatohepatitis (MASH). MASH progression is driven by insulin resistance, de novo lipogenesis and hepatic lipid accumulation, which promote lipid peroxidation and reactive oxygen species (ROS) generation. These insults contribute to mitochondrial injury and dysfunction, impairing oxidative phosphorylation (OXPHOS) and amplifying oxidative stress. Damaged mitochondria act as both sources and targets of cellular injury, further activating inflammatory pathways, including mitogen‐activated protein kinase (MAPK), and accelerating hepatocellular damage and fibrosis (adapted from Ota [109]).

FIGURE 8

Frequently studied genetic variants implicated in the pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD). Several gene variants have been associated with MASLD susceptibility, but key contributors with varying prevalence such as PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13, are among the most well‐characterised and strongly linked to disease progression. These variants impair hepatic lipid metabolism and have differing impacts on hepatic steatosis, metabolic dysfunction‐associated steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC) conferring varying relative risk [128].