EGCG inhibits ferroptosis to ameliorate APAP-induced liver injury by suppressing NEDD8 and stabilizing HUWE1 in vivo and in vitro

Abstract

Excessive consumption of acetaminophen (APAP) has emerged as the primary culprit behind drug-induced liver injury (DILI), with N-acetylcysteine serving as the principal antidote. However, use of N-acetylcysteine is limited to the early stages of APAP-induced DILI and may cause adverse side effects. Consequently, it is imperative to explore alternative therapeutic approaches to alleviate APAP-induced liver toxicity. In this study the mechanisms underlying the protective role of epigallocatechin gallate (EGCG) in DILI were determined. Our findings revealed that EGCG inhibited NEDD8, thus stabilizing HUWE1, a crucial E3 ubiquitin ligase involved in protein degradation. HUWE1 binds and degrades TFR1, a protein essential for cellular iron uptake and inhibits ferroptosis. By stabilizing HUWE1 and degrading TFR1, EGCG suppressed ferroptosis and ameliorated APAP-induced liver injury. Our results highlight the therapeutic potential of EGCG in mitigating DILI through regulation of HUWE1 and ferroptosis, which offers a promising approach for the treatment of DILI.

Keywords

EGCG / liver injury / NEDD8 / HUWE1 / ferroptosis

References

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