Metabolic dysfunction-related fatty liver disease: pathological mechanisms mediated by common and heterogeneous pathways

Abstract

BACKGROUND: In recent years, with the continuous maturity of the research system, metabolic dysfunction-related fatty liver disease has become independent from traditional non-alcoholic fatty liver disease. Its metabolic disorder background and heterogeneous disease progression patterns have updated the academic understanding of this type of disease. However, the relationship between the common occurrence mechanism of this type of disease and the pathological differences between individuals still needs to be further elucidated through systematic research. OBJECTIVE: To review the common pathways (such as insulin resistance and oxidative stress) commonly found in the pathological mechanism of metabolic dysfunction-related fatty liver disease, and to deeply explore its heterogeneous regulatory network (such as genetic variation and adipose tissue dysfunction), so as to analyze the interaction between the two. METHODS: A systematic search was conducted in Web of Science, PubMed, Embase, CNKI, Wanfang, and VIP databases for Chinese and English literature, with the search time limit from the establishment of each database to June 2025, focusing on the common metabolic disorder mechanisms, genetic/microenvironment heterogeneity pathways, and clinical phenotype classification of metabolic dysfunction-related fatty liver disease, sorting out relevant literature and integrating research evidence. RESULTS AND CONCLUSION: The pathological mechanism of metabolic dysfunction-related fatty liver disease revolves around the core of 'common pathways, heterogeneous regulation, dynamic interaction'. Among the common pathways, insulin resistance is the core link, which activates de novo lipogenesis in the liver, inhibits fatty acid oxidation, and jointly leads to abnormal lipid deposition in hepatocytes; activates the nuclear factor kappa B inflammatory pathway to aggravate hepatocyte injury, and upregulates the transforming growth factor beta pathway to promote liver fibrosis. The synergistic effects of oxidative stress and redox imbalance, and excessive fatty acid accumulation impair mitochondrial function, increase reactive oxygen species production, and destroy cell structure, while an imbalanced state (such as abnormal beta-hydroxybutyrate/acetoacetate ratio) further aggravates injury and promotes the progression of metabolic dysfunction-related fatty liver disease. In terms of heterogeneous regulation, PNPLA3 I148M inhibits triglyceride hydrolysis, TM6SF2 E167K reduces very low-density lipoprotein precursor secretion, independently driving the risk of metabolic dysfunction-related fatty liver disease, liver fibrosis, and cancer; adipose tissue dysfunction is key in lean metabolic dysfunction-related fatty liver disease, leading to ectopic fat deposition and decreased adiponectin levels; among the three metabolic subtypes, type A has lower cardiovascular risk, while types B/C progress rapidly in liver fibrosis. Therefore, the dynamic interaction between genetics, metabolism, and environment affects the disease trajectory, and differentiated intervention based on metabolic subtypes and genetic metabolic risk scores can provide theoretical support for precise risk stratification and personalized treatment of metabolic dysfunction-related fatty liver disease.

1. Introduction

Metabolic dysfunction-related fatty liver disease (MAFLD) is characterized by excessive fat deposition in hepatocytes, accompanied by insulin resistance, abnormal lipid metabolism, and systemic inflammation [1]. In recent years, with the continuous maturity of the research system, the metabolic disorder background and heterogeneous disease progression patterns of MAFLD have updated the academic understanding of this disease [2].

The core pathological mechanism of MAFLD originates from systemic imbalance of the metabolic network. As the core of the common mechanism, insulin resistance plays a key driving role in the pathological process: it not only activates de novo lipogenesis in the liver, but also inhibits fatty acid oxidation, ultimately leading to abnormal lipid accumulation in hepatocytes [3]. Meanwhile, oxidative stress and redox imbalance aggravate hepatocyte injury caused by fat deposition, activating inflammatory signaling pathways such as nuclear factor kappa B, and promoting the progression of MAFLD to steatohepatitis, liver fibrosis, and even cirrhosis [4]. These common mechanisms constitute the basic framework of the pathological process of MAFLD, but clinical observations reveal significant individual differences in disease phenotype, progression rate, and complication risk, indicating that the disease also has complex heterogeneous regulatory pathways [5].