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

Liver-specific deletion of MARCHF6 in mice increases SREBP1 protein levels and prolongs its half-life, driving excessive de novo lipogenesis under normal chow and diet-induced MASLD.

• Why it matters: SREBP1 turnover mechanisms in metabolic dysfunction-associated steatotic liver disease are unclear, and ERAD’s role in hepatic lipid control remains elusive.
• What they did: The study generated liver-specific Marchf6 knockout (Marchf6 Alb ) mouse cell lines and organoids, used RNA sequencing and proteomics, and tested SREBP1 regulation in primary hepatocytes, human hepatoma cells, and organoids.
• The result: MARCHF6 directly interacted with and ubiquitinated SREBP1 for proteasomal degradation; its loss aggravated hepatic lipid accumulation, fibrosis, and inflammation, and MARCHF6 restoration largely reversed these phenotypes.

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