METTL7A is a key regulator of hepatic lipid metabolism and nonalcoholic fatty liver disease progression

Methyltransferase-like protein 7A (METTL7A), an m 6 A RNA methyltransferase and thiol methyltransferase enriched in hepatocytes, has been implicated in cancer biology, yet its role in hepatic lipid metabolism and nonalcoholic fatty liver disease (MASLD/NAFLD) remains unknown. Hepatic steatosis was induced in HepG2 and Huh7 cells using oleic acid (OA). The role of METTL7A was examined through shRNA-mediated knockdown, RNA sequencing, lipid metabolic assays, and rescue experiments. Protein interactions were assessed via mass spectrometry and co-immunoprecipitation. An AAV-shMETTL7A mouse MASLD/NAFLD model was used to validate in vivo relevance. METTL7A expression was significantly upregulated in OA-induced steatotic hepatocytes. METTL7A silencing mitigated lipid accumulation, improved cell viability, reduced LDL-C, TC, and TG levels, and restored HDL-C. Transcriptomic profiling identified PLIN5 as a key downstream target reduced upon METTL7A depletion. Mechanistically, METTL7A knockdown inhibited PI3K/AKT activation and suppressed PLIN5 expression. Mass spectrometry revealed SAPCD2 as a METTL7A-interacting protein, and SAPCD2 overexpression restored lipid accumulation, PI3K/AKT activation, and PLIN5 levels in METTL7A-deficient cells. In vivo, AAV-mediated METTL7A knockdown alleviated hepatic steatosis, normalized serum lipid profiles and liver injury markers, and reduced SAPCD2, PLIN5, FAS, and ACC while increasing HSL expression. METTL7A is a previously unrecognized regulator of hepatic lipid homeostasis that promotes steatosis by sustaining SAPCD2 expression and activating the PI3K/AKT pathway and PLIN5 expression. Targeting METTL7A may represent a promising therapeutic strategy for MASLD/NAFLD.