SIK1 promotes ferroptosis resistance in pancreatic cancer via HDAC5-STAT6-SLC7A11 axis

  • Cancer Lett. 2025 Jul 28:623:217726. doi: 10.1016/j.canlet.2025.217726.
Hao Zhang  1 ,  Tao Ma  1 ,  Xiaofeng Wen  2 ,  Jianlong Jiang  3 ,  Jing Chen  2 ,  Junfeng Jiang  1 ,  Jiancong Xie  4 ,  Taiwei Mo  4 ,  Ruibing Li  2 ,  Hanlin Xie  2 ,  Guanzhan Liang  2 ,  Lin Wang  2 ,  Zheyu Zheng  1 ,  Xiaoming Huang  1 ,  Chuanyuan Liu  5 ,  Yimamu Baihetiyaer  6 ,  Abuduhalike Abulimiti  7 ,  Xiaosheng He  8 ,  Zexian Chen  9 ,  Tuo Hu  10 ,  Weidong Pan  11
Affiliations
  • 1. Department of General Surgery (Pancreatic Hepatobiliary Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2. Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3. Department of Gastrointestinal Surgery, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
  • 4. Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
  • 5. Department of General Surgery, The Ganzhou People's Hospital, Ganzhou, China.
  • 6. Department of General Surgery, The First People's Hospital of Kashgar Region, Kashgar, China.
  • 7. Department of General Surgery, The Second People's Hospital of Kashgar Region, Kashgar, China.
  • 8. Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 9. Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 10. Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 11. Department of General Surgery (Pancreatic Hepatobiliary Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
PMID: 40250791 DOI: 10.1016/j.canlet.2025.217726
Abstract

The activation of protein kinases is ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet its impact on Ferroptosis remains unclear. SIK1 was identified as a key regulator of Ferroptosis resistance in PDAC by kinase database screening. Targeting SIK1 could significantly reverse Ferroptosis resistance and enhance cytotoxic effects of gemcitabine via increasing Ferroptosis sensitivity in PDAC cells. Mechanistically, SIK1 phosphorylated HDAC5 at Ser498 residue and promoted its interaction with 14-3-3 protein, which further protected HDAC5 from TRIM28-mediated ubiquitylation and degradation. SIK1-stabilized HDAC5 deacetylated STAT6 and enhanced its transcriptional activity to upregulate SLC7A11 expression, ultimately rendering PDAC cells resistance to Ferroptosis. SIK1 Inhibitor (YKL-05-099) could synergistically enhance the antitumor effects of gemcitabine in Organoid and patient-derived xenograft (PDX) models by inducing Ferroptosis, suggesting a novel therapeutic target for PDAC. Clinically, SIK1 was positively correlated with SLC7A11 expression in PDAC specimens, which was associated with poor prognosis. These findings unveil a crucial mechanism through which PDAC counters Ferroptosis via SIK1-mediated HDAC5 stabilization and subsequent SLC7A11 upregulation. This study underscores the promising potential of targeting SIK1-HDAC5 axis as a therapeutic strategy to overcome drug resistance in PDAC.

Keywords
Histone deacetylase 5; Kinase signaling; Lipid peroxidation; Oxidative stress response; PDAC.
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