The OAS1-FASN axis promotes pancreatic cancer by coordinating lipogenic stress and the unfolded protein response.

Metabolic reprogramming, characterized by dysregulated lipid metabolism and consequent endoplasmic reticulum (ER) stress, constitutes a hallmark of pancreatic ductal adenocarcinoma (PDAC). Within this metabolic landscape, the 2'-5'-Oligoadenylate Synthetase (OAS) family member OAS1 is identified as a critical driver of malignancy, exhibiting specific upregulation in PDAC tissues that correlates with poor patient prognosis. Functionally, OAS1 drives tumor progression, including cell proliferation and metastasis, by operating as a non-canonical metabolic regulator. Mechanistically, OAS1 binds to fatty acid synthase (FASN), maintaining its functional protein levels and thereby promoting FASN-dependent lipid synthesis. The resulting surge in de novo lipid synthesis and lipid droplet accumulation precipitates an adaptive ER stress response via the PERK-ATF4 signaling axis. Consequently, a functional OAS1-FASN axis operates to coordinate lipid overload with pro-survival ER stress signaling, establishing OAS1 as a pivotal metabolic regulator and a viable biomarker in PDAC.