Targeting phospholipase Pla2g15 reduces long-chain BMP phospholipids abundance and senescence in kidney cells.

Chronic kidney disease (CKD), a major age-related pathology, is driven by the accumulation of chronic senescent proximal tubular epithelial cells (TECs), promoting fibrosis and functional decline. Although senescence involves metabolic reprogramming, the role of complex lipid metabolism in TECs senescence remains poorly understood. Here, we identify a critical role for lysosomal phospholipid metabolism in senescent TECs. We show that the lysosomal phospholipid bis(monoacylglycerol)phosphate (BMP) increases during kidney aging and in senescent TECs. Genetic knockout of the BMP hydrolase Pla2g15 in TECs elevated total lysophosphatidylglycerol (LPG) and BMP, with a notable shift in BMP species. Long-chain unsaturated BMPs, which accumulate during doxorubicin-induced senescence in TECs, were specifically reduced in Pla2g15-deficient cells, whereas wild-type TECs showed increased levels upon senescence induction. Pla2g15 knockout also provided significant protection against doxorubicin-induced senescence. Proteomic profiling revealed that this protection was linked to enhanced mitochondrial metabolism, including NAD+ metabolism and fatty acid oxidation. These findings demonstrate that PLA2G15 contributes to TEC senescence through selective BMP lipid remodelling and regulation of mitochondrial function. Targeting PLA2G15 therefore may represent a promising therapeutic strategy to prevent senescence and the associated burden of CKD progression.