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

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.