MARCHF6 orchestrates hepatic lipid homeostasis by targeting SREBP1 for ER-associated degradation

BACKGROUND & AIMS: Increased de novo lipogenesis, largely mediated by sterol regulatory element-binding protein 1 (SREBP1), is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the post-translational mechanisms regulating SREBP1 turnover remain poorly understood. The endoplasmic reticulum-associated degradation (ERAD) pathway ensures protein quality and quantity control, yet its role in hepatic lipid metabolism remains elusive. Here, we investigate the function of the ERAD-specific E3 ubiquitin ligase MARCHF6 in hepatic lipid homeostasis and MASLD pathogenesis.

METHODS: Liver-specific Marchf6 knockout (Marchf6 Alb) mouse cell lines and organoids were generated to assess the impact of Marchf6 depletion on hepatic lipid metabolism under normal chow, high-fat diet, and Western diet conditions. RNA sequencing, proteomics, biochemical and molecular biological analyses were performed to identify molecular pathways regulated by MARCHF6. Functional studies in primary hepatocytes, human hepatoma cells and organoids were conducted to determine the mechanistic link between MARCHF6 and SREBP1.

RESULTS: Hepatic MARCHF6 expression was significantly reduced in both MASLD mouse models and human patients. Liver-specific Marchf6 deletion aggravated hepatic lipid accumulation, fibrosis, and inflammation. Transcriptomic and proteomic analyses revealed upregulation of lipogenic genes in Marchf6 Alb livers, with a marked increase in SREBP1 protein levels. Mechanistically, MARCHF6 directly interacted with and ubiquitinated SREBP1, targeting it for proteasomal degradation. Loss of MARCHF6 prolonged SREBP1 half-life, driving excessive de novo lipogenesis.

CONCLUSIONS: MARCHF6-ERAD is a critical regulator of hepatic lipid metabolism, functioning as a sterol binding protein to control SREBP1 turnover. Its downregulation promotes hepatic steatosis and MASLD progression, highlighting MARCHF6 as a potential therapeutic target in MASLD.

IMPACT AND IMPLICATIONS: This study identifies the endoplasmic reticulum-resident E3 ubiquitin ligase MARCHF6 as a key regulator of SREBP1 stability, hepatic lipid homeostasis and MASLD (metabolic dysfunction-associated steatotic liver disease) progression. We demonstrate that loss of MARCHF6 promotes hepatic steatosis and fibrosis, whereas restoration of MARCHF6 largely reverses these phenotypes, highlighting a reversible and therapeutically targetable pathway. These findings provide new mechanistic insight into lipid dysregulation in MASLD and position the MARCHF6-SREBP1 axis as a promising target for metabolic liver disease intervention.