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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\u2010fat diet\u2010fed mice reduced hepatic lipid droplet size without altering the levels of serum triglycerides and fasting blood glucose. Suppression of liver\u2010specific\n                    <jats:italic>Pla2g6<\/jats:italic>\n                    utilizing the short\u2010hairpin RNA knockdown technique using an adenovirus vector (Ad\u2010shPLA2G6) altered phospholipid and fatty acid metabolites and suppressed hepatic lipid accumulation, serum triglyceride, fasting glucose, and insulin levels. Additionally, Ad\u2010shPLA2G6 treatment downregulated lipid biosynthesis\u2010related genes but upregulated peroxisomal fatty acid oxidation\u2010related genes. These findings indicate that targeting hepatic\n                    <jats:italic>Pla2g6<\/jats:italic>\n                    modulates phospholipid and fatty acid metabolites and improves glucose and lipid metabolism, suggesting\n                    <jats:italic>Pla2g6<\/jats:italic>\n                    as a potential therapeutic target in metabolic disorders, including type 2 diabetes mellitus and metabolic dysfunction\u2010associated steatotic liver disease.\n                  <\/jats:p>","DOI":"10.1096\/fj.202504753rr","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T13:49:12Z","timestamp":1776692952000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Liver\u2010Specific Suppression of\n                    <scp>PLA2G6<\/scp>\n                    \/\n                    <scp>\n                      iPLA\n                      <sub>2<\/sub>\n                      \u03b2\n      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