Rethinking LPCAT3 roles in human disease: broadening perspectives beyond ferroptosis

Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a membrane-bound O-acyltransferase, is well known for enriching phospholipids (PLs) with polyunsaturated fatty acids (PUFAs) and thereby driving ferroptosis. However, accumulating evidence indicates that LPCAT3 is not merely a ferroptosis effector but a broader integrator of non-ferroptotic functions, such as autophagy, endoplasmic reticulum homeostasis, and inflammatory signaling. Herein, we provide an overview of LPCAT3 functions that explicitly extend beyond ferroptosis. We first provide a comprehensive review of the structural and enzymatic characteristics of LPCAT3, along with its diverse regulatory mechanisms of expression. Subsequently, we summarize how LPCAT3-mediated PL remodeling modulates membrane biophysical properties and further elucidate the downstream effects of this remodeling on the regulation of autophagy, endoplasmic reticulum homeostasis, and inflammatory signaling pathways. Finally, we systematically review the pivotal roles of LPCAT3 in the pathogenesis of multiple human diseases, including neurodegenerative diseases, stroke, atherosclerosis (AS), diabetes mellitus, obesity (OB), non-alcoholic fatty liver disease (NAFLD), and cancer. This review aims to elucidate the functions of LPCAT3 beyond its role in regulating ferroptosis and may provide new insights into its involvement in human diseases.