ACSL5 drives pancreatic ductal adenocarcinoma by suppressing mitophagy and enhancing ferroptosis resistance via the...

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options. Here, we identify long-chain acyl-CoA synthetase 5 (ACSL5) as a key oncogenic driver and prognostic biomarker in PDAC. Combined transcriptomic analysis of 51 PDAC samples and three public databases (GSE183795, GSE28735, GSE62452) reveals that ACSL5 is markedly upregulated in PDAC, and its overexpression is significantly associated with shorter patient survival and high diagnostic accuracy (AUC = 0.899), suggesting robust diagnostic potential. Functional assays demonstrate that ACSL5 promotes PDAC cell proliferation, migration, and tumor growth while inhibiting apoptosis. Mechanistically, ACSL5 activates the JAK1-STAT1 signaling pathway, leading to transcriptional upregulation of oligoadenylate synthetase-like protein (OASL). The ACSL5-OASL axis concurrently suppresses PINK1/Parkin-mediated mitophagy and enhances ferroptosis resistance by modulating GPX4, SLC7A11, and ACSL4 expression. Notably, the mitophagy activator CCCP effectively reverses ACSL5-driven tumor progression and restores ferroptosis sensitivity. Our findings establish ACSL5 as a promising diagnostic and therapeutic target and reveal that targeting mitophagy represents a potential strategy for ACSL5-high PDAC.