LPCAT3 as a Potential Drug Target for Ultraviolet Radiation-Induced Cataract: Insights From Multiomics Analysis.

Ultraviolet B (UVB) radiation is a major risk factor for cataract development, but the molecular mechanisms underlying this process, particularly the involvement of regulated cell death pathways such as ferroptosis, remain unclear. Transcriptomic, proteomic, and metabolomic analyses were performed on lens tissues from UVB-induced cataract rat models and controls to identify differentially expressed genes (DEGs), proteins (DEPs), and metabolites. Integrated bioinformatic analysis was then used to identify key pathways and molecules. The role of the top candidate gene, lysophosphatidylcholine acyltransferase 3 (LPCAT3), was further investigated in vitro in rat lens epithelial cells (LECs) exposed to UVB and in vivo using an Ad5-shLPCAT3 knockdown model. Multiomics analysis identified 1787 DEGs and 355 DEPs between cataractous and normal rat lenses. KEGG enrichment highlighted pathways including complement/coagulation cascades, cell cycle, mineral absorption, and glycerophospholipid metabolism. Metabolomic analysis revealed 2332 significantly altered metabolites enriched in sphingolipid, purine, and glycerophospholipid metabolism. Integrated analysis revealed that expression of LPCAT3, a key enzyme in glycerophospholipid metabolism, was significantly upregulated. UVB irradiation of LECs induced ferroptosis, which was characterized by decreased viability, increased ROS, MDA, 4HNE, and ACSL4 expression; decreased GPX4 expression; and upregulated LPCAT3 expression. LPCAT3 knockdown significantly protected LECs against UVB-induced cell death, ROS production, lipid peroxidation, and ferroptosis marker dysregulation. Ad5-shLPCAT3 injection attenuated UVB-induced lens opacification, decreased ROS/MDA levels, and reversed ferroptosis-related protein changes in vivo. This study demonstrated that LPCAT3 upregulation drives ferroptosis in LECs and that targeting LPCAT3 effectively mitigates UVB-induced LEC ferroptosis and cataract formation in vivo, highlighting its therapeutic potential.