Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, in which the role of lipophagy, a selective autophagic process degrading lipid droplets (LDs), remains poorly characterized. This study investigated lipophagy and its key regulator, OSBPL10, in PDAC progression. Through immunofluorescence analysis of patient samples, transgenic mouse tissues, and cell lines, we find that lipophagy is elevated in PDAC and correlates with poor prognosis. Single-cell transcriptomic analysis identified OSBPL10 as a critical lipophagy regulator and an independent clinicopathological indicator. Functional assays, including orthotopic and subcutaneous xenografts, demonstrated that OSBPL10 promotes tumor growth. Mechanistically, OSBPL10 functionally cooperates with VAPA/VAPB to facilitate rapid lysosomal repair via ATG2A, thereby promoting lipophagy and lipid mobilization. Inhibition of lysosomal function abrogated the pro-lipophagic and pro-tumorigenic effects of OSBPL10. Collectively, our findings demonstrate that upregulated OSBPL10 drives PDAC progression by enhancing lipophagy through ATG2A-mediated rapid lysosomal repair, highlighting OSBPL10 as a potential therapeutic target in PDAC.