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
  • 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: [email protected].
  • 5. Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, China. Electronic address: [email protected].
  • 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: [email protected].
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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