2. Academic Validation
  3. DTL dose-dependent control of sex-dimorphic ferroptosis in liver ischemia reperfusion injury

DTL dose-dependent control of sex-dimorphic ferroptosis in liver ischemia reperfusion injury

  • Cell Rep. 2025 Jul 22;44(7):115920. doi: 10.1016/j.celrep.2025.115920.
Xiang Huang 1,  Junfu Fan 1,  Kunxuan Zhu 1,  Xiangjun Wu 1,  Chunhui Jiang 1,  Junhao Chen 1,  Jiebin Qiu 1,  Lian Duan 2,  Zhicheng Hu 1,  Xixi Chen 3,  Bin Zhou 4,  Jingling Shen 5,  Weitao Cong 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutica Science, Wenzhou Medical University, Wenzhou, People's Republic of China.
  • 2 Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 3 Department of Pharmacy, Taizhou Central Hospital, Taizhou, Zhejiang, China.
  • 4 Department of Hepatobiliary Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: zb195058@sina.com.
  • 5 Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, China. Electronic address: jingling_shen@wzu.edu.cn.
  • 6 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutica Science, Wenzhou Medical University, Wenzhou, People's Republic of China. Electronic address: cwt97126@126.com.
PMID: 40560731 DOI: 10.1016/j.celrep.2025.115920
Abstract

Hepatic ischemia/reperfusion (I/R) injury is a typically sexually dimorphic disease, and males are more vulnerable to I/R injury than females are. However, the molecular basis of the sex-based differences remains poorly defined. Here, using multi-omics integrative analysis, we identified the denticleless E3 ubiquitin protein Ligase (DTL)-homeobox protein prospero-related homeobox 1 (PROX1) signaling axis as a key determinant of the sexual dimorphism associated with hepatic I/R injury. High post-hepatectomy DTL levels were accompanied by deteriorated hepatectomy patient function and correlated with augmented hepatocellular death. DTL was markedly up-regulated in hepatocytes during hepatic I/R injury, and it ubiquitinated and degraded PROX1. This triggered an increase in polyunsaturated fatty acid (PUFA) levels, eventually leading to Ferroptosis and exacerbated liver damage. Furthermore, the sex-specific differential expression of DTL in mice resulted in sex disparity of I/R-induced Ferroptosis. Taken together, the results of this study have revealed Ferroptosis involving a DTL-PROX1 axis that functionally determines sexual dimorphism in hepatic I/R injury.

Keywords

CP: Metabolism; DTL; PROX1; ferroptosis; hepatic ischemia/reperfusion injury; sexual dimorphism.

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