Upregulation of FAT10 by TLR4/NF-kappaB pathway contributes to MASLD development by the modulation of FASN stability and mitophagy

Human leukocyte antigen-F adjacent transcript 10 (FAT10) is a ubiquitin-like protein implicated in various chronic pathological conditions. However, its functional contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) progression remains poorly defined. This study aimed to clarify the role of FAT10 in the development of MASLD. Public transcriptomic data from Gene Expression Omnibus (GEO) were analyzed to assess the association between FAT10 expression and MASLD severity. Mice transduced with adeno-associated virus 8 (AAV8)-mediated Control (AAV8-Ctrl) or human FAT10 (AAV8-FAT10) were fed either a high-fat, high-cholesterol (HFHC) diet or a normal chow diet (NCD) to investigate the role of FAT10 in MASLD development in vivo. HepG2 and Huh7 cell lines were employed as in vitro models to investigate the molecular mechanisms by which FAT10 aggravates MASLD, with a focus on fatty acid synthase (FASN) regulation and mitophagy. FAT10 mRNA expression was markedly increased in liver tissues from patients with MASLD and showed a positive correlation with NAFLD activity scores. Consistently, hepatic FAT10 expression was significantly elevated in HFHC-fed mice compared with NCD-fed controls. Transduction of AAV8-FAT10 substantially deteriorated HFHC-induced hepatic steatosis, inflammation and fibrosis. Subcellular localization analysis revealed that FAT10 was associated with the mitochondrial compartment, while biochemical analyses identified FASN as a FAT10-interacting protein. Mechanistically, FAT10 interacted with FASN and suppressed its ubiquitin-dependent proteasomal degradation. In addition, FAT10 impaired mitochondrial quality control by suppressing mitophagy. FAT10 is upregulated in MASLD and promotes disease progression by stabilizing FASN and inhibiting mitophagy. FAT10 represents a potential molecular target for future MASLD intervention.