2. Academic Validation
  3. SMAD4 Palmitoylation Drives a Metabolic-Transcriptional Circuit to Promote Tumorigenesis and Confers Radiosensitivity in Pancreatic Cancer

SMAD4 Palmitoylation Drives a Metabolic-Transcriptional Circuit to Promote Tumorigenesis and Confers Radiosensitivity in Pancreatic Cancer

  • Adv Sci (Weinh). 2026 Mar 26:e19791. doi: 10.1002/advs.202519791.
Yang Wang 1 2,  Shan Zhang 3,  Junping Bai 3,  Xiaobing Li 4,  Yi Han 3,  Min Ji 2,  Chongyi Jiang 5,  Xiaobei Ge 6,  Tianyu Yu 7,  Yongying Hou 8,  Jun Zhang 9,  Wangting Li 10,  Yiran Song 11,  Jiaying Cai 12,  Yingqun Zhou 1,  Liwei An 3 10,  Feng Wang 2
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 YangPu District Mental Health Center, Shanghai University of Medicine & Health Sciences, Shanghai, China.
  • 3 Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Shanghai, China.
  • 4 Center For Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai, China.
  • 5 Department of Hepato-Biliary-Pancreatic Surgery, Huadong Hospital, Fudan University, Shanghai, China.
  • 6 Department of Nursing, Huadong Hospital, Fudan University, Shanghai, China.
  • 7 Hepatobiliary Surgery Center, Shanghai Tongji Hospital Affiliated to Tongji University, Tongji University, Shanghai, China.
  • 8 Department of Pathology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
  • 9 International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China.
  • 10 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 11 Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  • 12 Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
PMID: 41885390 DOI: 10.1002/advs.202519791
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent SMAD4 inactivation and profound lipid metabolic rewiring, yet how these processes intersect especially in SMAD4+ PDAC remains elusive. Here, we identify palmitoylation as a previously unrecognized post-translational modification of SMAD4. Combining biochemical labeling, mutagenesis, and functional assays, we demonstrate that SMAD4 is palmitoylated at cysteine 363 by the Acyltransferase ZDHHC22 and depalmitoylated by APT2. Mechanistically, palmitoylation enhances SMAD4 protein stability, facilitates the interaction of SMAD4 with importins, and amplifies subsequent transcriptional output, leading to direct upregulation of the key fatty acid biosynthetic enzyme FASN. Consequently, elevated palmitic acid levels in turn reinforce SMAD4 palmitoylation, establishing a self-amplifying SMAD4 palmitoylation-FASN-palmitic acid positive feedback loop that drives PDAC tumor growth. Intriguingly, SMAD4 palmitoylation sensitizes PDAC cells to radiotherapy both in vitro and in vivo, revealing a dual role between tumor progression and treatment responses. Notably, clinically relevant SMAD4 mutants (R361C and R361H) exhibit enhanced palmitoylation, underscoring the pathological relevance of this mechanism for tumorigenesis. Collectively, these findings unveil a metabolic-transcriptional circuit wherein palmitoylation bridges lipid metabolism with SMAD4-driven oncogenesis, and posit SMAD4 palmitoylation as a therapeutic vulnerability in pancreatic Cancer.

Keywords

FASN; SMAD4; palmitic acid; palmitoylation; pancreatic cancer; radiotherapy.

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