PLA2G12B (phospholipase A2 group XIIB) is a hepatic and intestinal protein involved in lipid metabolism that lacks canonical catalytic activity. In the liver, PLA2G12B functions as a key mediator of very-low-density lipoprotein (VLDL) secretion and triglyceride homeostasis 1. Its expression is transcriptionally regulated by hepatocyte nuclear factor 4-alpha (HNF4α) and estrogen-related receptor gamma (ERRγ), both of which bind to the PLA2G12B promoter 2. In the intestine, PLA2G12B plays a critical role in chylomicron expansion and lipidation at the endoplasmic reticulum, contributing to dietary lipid absorption and transport 34. Pharmacologically, activation of the farnesoid X receptor suppresses PLA2G12B expression through HNF4α inhibition, resulting in reduced serum triglycerides and hepatic VLDL-TG secretion 5. Disease relevance includes atherosclerotic cardiovascular disease (ASCVD), where PLA2G12B downregulation through PSRC1 activation shows therapeutic potential for coronary artery disease 6. Additionally, PLA2G12B upregulation appears beneficial in type 2 diabetes management by alleviating hepatic lipotoxicity 7. These findings identify PLA2G12B as a promising pharmaceutical target for dyslipidemia and related cardiometabolic disorders.