biostudies-literatureTian XNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)823https://www.ebi.ac.uk/biostudies/studies/S-EPMC9512921biostudies-literatureUnknown13(9)Liver ischemia/reperfusion (I/R) injury is a major clinical concern of liver transplantation, which accounts for organ rejection and liver dysfunction. The adaptor protein p66Shc acts as a crucial redox enzyme and is implicated in liver I/R. Elevated p66Shc expression is associated with hepatocellular apoptosis in liver I/R, but the molecular mechanisms of p66Shc responsible for its aberrant expression and function remain unknown. In the present study, hepatocyte-specific p66Shc-knockdown mice exhibited clear inhibition in hepatocellular apoptosis and oxidative stress under liver I/R, while hepatocyte-specific p66Shc overexpression mice displayed the deteriorative impairment. Mechanistically, p66Shc-triggered mitochondrial fission and apoptosis in liver I/R by mediating ROS-driven Drp1 actCell death & diseaseUSP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion.PMC951292181721091Zhou LYang ZTian XZheng SZhao YLu QfalseUSP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion.Liver ischemia/reperfusion (I/R) injury is a major clinical concern of liver transplantation, which accounts for organ rejection and liver dysfunction. The adaptor protein p66Shc acts as a crucial redox enzyme and is implicated in liver I/R. Elevated p66Shc expression is associated with hepatocellular apoptosis in liver I/R, but the molecular mechanisms of p66Shc responsible for its aberrant expression and function remain unknown. In the present study, hepatocyte-specific p66Shc-knockdown mice exhibited clear inhibition in hepatocellular apoptosis and oxidative stress under liver I/R, while hepatocyte-specific p66Shc overexpression mice displayed the deteriorative impairment. Mechanistically, p66Shc-triggered mitochondrial fission and apoptosis in liver I/R by mediating ROS-driven Drp1 act2022-01-01T00:00:00Z2022 Sep2025-04-22T06:24:48.316Z2025-04-05T21:41:47.722ZS-EPMC95129213616317010.1038/s41419-022-05277-8