DTL dose-dependent control of sex-dimorphic ferroptosis in liver ischemia reperfusion injury
Xiang Huang, Junfu Fan, Kunxuan Zhu, Xiangjun Wu, Chunhui Jiang, Junhao Chen, Jiebin Qiu, Lian Duan, Zhicheng Hu, Xixi Chen, Bin Zhou, Jingling Shen, Weitao Cong
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.