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

Methyltransferase-like protein 7A (METTL7A), an m6A 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.