Deficiency of LPCAT3 Compromises Endometrial Stromal Cell Decidualization in Polycystic Ovary Syndrome

ABSTRACT Lysophosphatidylcholine acyltransferase 3 (LPCAT3) is a key enzyme in phospholipid metabolism and plays a crucial role in the reacylation phase of the Lands' cycle. This study explores the relationship between LPCAT3 and the abnormal decidualization of human endometrial stromal cells (hESCs) in polycystic ovary syndrome (PCOS), a condition associated with an increased risk of pregnancy complications and miscarriage. Our results showed that LPCAT3 expression was significantly lower in hESCs obtained from PCOS patients compared to controls. The knockdown of LPCAT3 in hESCs led to a decrease in the expression of decidual markers and a halt in the characteristic epithelioid‐like morphological changes indicative of decidualization. In contrast, overexpression of LPCAT3 had the opposite effect. The knockdown of LPCAT3 altered the phospholipid profile, notably reducing the levels of phosphatidylcholine (PC) (16:0‐20:4). Additionally, LPCAT3 knockdown slowed cell cycle progression and accelerated hESCs senescence. Importantly, reintroducing PC(16:0‐20:4) could counteract the decidualization defects and premature senescence caused by LPCAT3 knockdown. These findings suggest that LPCAT3 plays a previously unrecognized role in facilitating the decidualization process for successful pregnancy. This study identifies LPCAT3 as a potential therapeutic target for improving pregnancy outcomes in PCOS by influencing lipid composition and cellular senescence in hESCs, revealing a possible mechanism underlying decidualization deficiencies in PCOS.