DHRS9 knockdown attenuates severe acute pancreatitis by inhibiting ferroptosis through the modulation of redox homeostasis and oxylipin metabolism

  • Int Immunopharmacol. 2026 Sep 15:185:117035. doi: 10.1016/j.intimp.2026.117035.
Tingfeng Yu  1 ,  Ning Tan  1 ,  Mingzhe Ma  1 ,  Jingwen Wang  1 ,  Juanfei Peng  1 ,  Lingyun Wang  2
Affiliations
  • 1. Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
  • 2. Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: [email protected].
PMID: 42296784 DOI: 10.1016/j.intimp.2026.117035
Abstract

Background: Severe acute pancreatitis (SAP) is an acute and life-threatening systemic inflammatory pancreatic disease with mortality rates of up to 30%. DHRS9 is a short-chain dehydrogenase/reductase that regulates redox reactions and lipid metabolism. This study aimed to investigate the potential mechanism of DHRS9 in SAP.

Methods: DHRS9 expression was assessed through integrated bioinformatics analysis and validated in human SAP pancreatic tissue samples as well as in experimental models of SAP. The role of DHRS9 in inflammation and Ferroptosis was investigated in both in vitro and in vivo SAP models. High-throughput targeted metabolomics of oxylipin was utilized to elucidate the mechanism of DHRS9 in SAP.

Results: DHRS9 was identified as a ferroptosis-related gene by integrated bioinformatic analysis. High expression of DHRS9 was measured in the pancreatic tissues of SAP patients and in both in vitro and in vivo models. DHRS9 knockdown alleviated Ferroptosis and inflammation in both cellular and animal models, as indicated by decreased secretion of proinflammatory mediators and amylase activity, improved cell viability, reduced tissue damage, and reversed behaviour of ferroptosis-related biological indicators and proteins. Contrasting results were observed when DHRS9 was overexpressed. Mechanistically, DHRS9 knockdown significantly increased the cellular NAD+/NADH ratio, attenuating inflammatory responses and suppressing Ferroptosis in an in vitro model. DHRS9 deficiency inhibited Ferroptosis under inflammatory conditions by reprogramming oxylipin metabolism and enhancing mitochondrial β-oxidation through the modulation of NAD+ homeostasis.

Conclusion: DHRS9 could serve as a promising therapeutic target for SAP by regulating Ferroptosis through the modulation of cellular redox status and oxylipin profiling.

Keywords
DHRS9; Ferroptosis; Lipid peroxidation; NAD(+); Severe acute pancreatitis.
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