Role of MET and EGFR in acetaminophen-induced liver injury and regeneration-Role of MET and EGFR in acetaminophen-induced injury and regeneration

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Video Summary

Dr. Bharat Bhushan presented his extensive research on the roles of MET and EGFR receptor tyrosine kinases in acetaminophen-induced liver injury and liver regeneration, highlighting their distinct effects despite similarities in promoting hepatocyte proliferation. Using mouse models of acetaminophen overdose, a clinically relevant cause of acute liver failure, he found that MET activation serves as a protective survival mechanism that limits liver injury by inhibiting JNK (c-Jun N-terminal kinase) activation and mitochondrial damage, partly via AKT signaling. MET deletion increased liver injury, impaired glutathione replenishment, and decreased unfolded protein response, while reducing regeneration-associated gene expression.<br /><br />Conversely, EGFR activation, also early and dose-dependent, paradoxically aggravated liver injury. Pharmacological EGFR inhibition dramatically decreased liver damage by enhancing glutathione recovery, reducing prolonged JNK activation, and inducing autophagy and mitophagy, including TFEB-mediated lysosomal biogenesis. Hepatocyte-specific EGFR deletion also reduced injury progression and improved regeneration markers, likely secondary to decreased damage. Notably, combined MET and EGFR deletion showed no additive effects on injury or regeneration, suggesting opposing roles.<br /><br />Further investigations revealed that pan-EGFR family inhibitors reduced liver steatosis and fibrosis in a diet-induced MASLD model, effects not recapitulated by hepatocyte-specific EGFR deletion but observed with ERBB3 (HER3) deletion, implicating ERBB3 in lipid metabolism. Human ALF and MASLD datasets corroborated increased HGF/MET and NRG1/ERBB3 signaling respectively.<br /><br />The work underlines MET as protective and EGFR as injury-promoting in acetaminophen toxicity, with implications for therapeutic strategies combining EGFR inhibitors with N-acetylcysteine. Ongoing studies explore signaling crosstalk, off-target effects, roles in chronic liver diseases, and potential targeting of ERBB3 for steatosis treatment. The research is significant for understanding liver injury mechanisms and improving acute and chronic liver disease therapies.

Keywords

MET receptor tyrosine kinase

EGFR receptor tyrosine kinase

acetaminophen-induced liver injury

liver regeneration

JNK activation

AKT signaling

glutathione replenishment

autophagy and mitophagy

ERBB3 (HER3) signaling

therapeutic strategies for liver disease