ACSL5 suppresses pancreatic cancer progression and gemcitabine resistance by regulating n-6 docosapentaenoic acid metabolism

Gemcitabine (GEM) resistance remains a major challenge in pancreatic ductal adenocarcinoma (PDAC) treatment. Metabolic reprogramming is a hallmark of tumors, and imbalance in lipid metabolism promotes tumor progression and drug resistance. This study aims to elucidate the mechanism of Acyl-CoA Synthetase Long Chain Family Member 5 ( ACSL5 ) in PDAC, its impact on fatty acid metabolism, and its clinical relevance. Through RNA sequencing, targeted metabolomics, proteomics, retrospective cohort studies, and a series of in vitro and in vivo experiments, the significance of ACSL5 was systematically investigated. Our results showed that ACSL5 was downregulated in GEM-resistant cells, and its high expression predicted better survival in PDAC patients. ACSL5 overexpression suppressed proliferation, migration, invasion, and GEM resistance in PDAC cells, while its knockdown promoted these phenotypes. ACSL5 may exert its effects through the PPARδ/CPT1A signaling pathway, thereby influencing fatty acid β-oxidation. Notably, ACSL5 selectively modulated n-6 docosapentaenoic acid (DPA-n6) levels, while prospective cohort studies have shown that high plasma DPA-n6 is an independent risk factor for poor prognosis. Junction Plakoglobin (JUP) was identified as an ACSL5-binding protein and was associated with ACSL5 ubiquitination and protein stability. In summary, ACSL5 acts as a tumor suppressor in PDAC by modulating fatty acid metabolism. DPA-n6 may serve as a novel prognostic biomarker, highlighting the clinical relevance of ACSL5 -associated lipid metabolism in PDAC.