Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally prevalent chronic liver disorder for which effective therapeutic options are scarce. Autophagy is pivotal in sustaining hepatic lipid homeostasis, and cytoskeletal proteins modulate autophagic flux. However, the role of myosin heavy chain 11 (MYH11) in the pathogenesis of MASLD remains elusive. Bioinformatic mining of Gene Expression Omnibus (GEO) datasets identified MYH11 as a key autophagy-associated differentially expressed gene that exhibited robust diagnostic performance in MASLD. MYH11 expression was markedly downregulated in the livers of db/db mice and in the serum of patients with MASLD, and this reduction was negatively correlated with peripheral levels of alanine transaminase (ALT), total cholesterol (TC), triglycerides (TG), and LDL-C. Gain- and loss-of-function experiments validated MYH11's protective role : AAV8-mediated MYH11 overexpression mitigated hepatic steatosis, inflammation, and fibrosis in db/db mice and inhibited extracellular matrix (ECM) deposition in palmitic acid-challenged LX-2 cells and inflammatory responses in palmitic acid-challenged HepG2 cells, whereas MYH11 silencing exacerbated these pathological changes. Mechanistically, MYH11 boosts autophagic flux by upregulating ATG4A expression, and MYC directly interacts with the MYH11 promoter to regulate its transcriptional activity. In summary, MYH11 functions as a MYC-regulated protective factor in MASLD, alleviating hepatic damage via the MYH11-ATG4A-autophagy axis. Thus, it holds promise as a candidate diagnostic biomarker and prospective therapeutic target for MASLD.
