Shimizu_2026_Faseb.j_40_e71821

Phospholipase A2 group VI (PLA2G6, also called iPLA(2)beta) has been implicated in male fertility, neuronal disorders, and metabolic diseases. However, its therapeutic effects on metabolic disorders remain elusive. We investigated the effects of PLA2G6 suppression on glucose and lipid metabolism. Systemic inhibition of PLA2G6 in high-fat diet-fed mice reduced hepatic lipid droplet size without altering the levels of serum triglycerides and fasting blood glucose. Suppression of liver-specific Pla2g6 utilizing the short-hairpin RNA knockdown technique using an adenovirus vector (Ad-shPLA2G6) altered phospholipid and fatty acid metabolites and suppressed hepatic lipid accumulation, serum triglyceride, fasting glucose, and insulin levels. Additionally, Ad-shPLA2G6 treatment downregulated lipid biosynthesis-related genes but upregulated peroxisomal fatty acid oxidation-related genes. These findings indicate that targeting hepatic Pla2g6 modulates phospholipid and fatty acid metabolites and improves glucose and lipid metabolism, suggesting Pla2g6 as a potential therapeutic target in metabolic disorders, including type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease.