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journal article·2026-07Open access

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

Yang Wang, Shan Zhang, Junping Bai, Xiaobing Li, Yi Han, Min Ji, Chongyi Jiang, Xiaobei Ge, Tianyu Yu, Yongying Hou, Jun Zhang, Wangting Li, Yiran Song, Jiaying Cai, Yingqun Zhou, Liwei An, Feng Wang

Advanced Science· Volume 13· Issue 41
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Abstract

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.
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Research context

Composites

OpenAlex topics: Cancer, Lipids, and Metabolism · Cancer Research and Treatments · Ferroptosis and cancer prognosis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Gastroenterology Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai China

YangPu District Mental Health Center Shanghai University of Medicine & Health Sciences Shanghai China

Department of Stomatology Shanghai Tenth People's Hospital Tongji University Cancer Center Shanghai China

Center For Molecular Recognition and Biosensing School of Life Sciences Shanghai University Shanghai China

Department of Hepato‐Biliary‐Pancreatic Surgery Huadong Hospital Fudan University Shanghai China

Department of Nursing Huadong Hospital Fudan University Shanghai China

Hepatobiliary Surgery Center Shanghai Tongji Hospital Affiliated to Tongji University Tongji University Shanghai China

Department of Pathology Daping Hospital Army Medical University (Third Military Medical University) Chongqing China

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

School of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing China

Department of Gastroenterology Shanghai General Hospital Shanghai JiaoTong University School of Medicine Shanghai China

Department of Gastroenterology Huadong Hospital Shanghai Medical College Fudan University Shanghai China

Funding

Science and Technology Commission of Shanghai Municipality

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