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

  • Cell Death Dis. 2026 Jun 3. doi: 10.1038/s41419-026-08922-8.
Yuheng Zhu  #  1 ,  Hongfei Yao  #  1 ,  Chunjing Li  #  1 ,  Jie Peng  #  2 ,  Jieqiong Ge  3 ,  Meng Liu  1 ,  Tongyi Zhang  4 ,  Zhiwei Cai  5 ,  Chongyi Jiang  6  7
Affiliations
  • 1. Department of Hepato‑Biliary‑Pancreatic Surgery, General Surgery, Huadong Hospital, Fudan University, Shanghai, PR China.
  • 2. Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
  • 3. Department of Nursing, Huadong Hospital, Fudan University, Shanghai, PR China.
  • 4. Department of Hepato‑Biliary‑Pancreatic Surgery, General Surgery, Huadong Hospital, Fudan University, Shanghai, PR China. [email protected].
  • 5. Department of Hepato‑Biliary‑Pancreatic Surgery, General Surgery, Huadong Hospital, Fudan University, Shanghai, PR China. [email protected].
  • 6. Department of Hepato‑Biliary‑Pancreatic Surgery, General Surgery, Huadong Hospital, Fudan University, Shanghai, PR China. [email protected].
  • 7. Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, PR China. [email protected].
  • # Contributed equally.
PMID: 42236684 DOI: 10.1038/s41419-026-08922-8
Abstract

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.

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