Cuproptosis Is Induced in Drug-Induced Liver Injury by Oxidative Stress-Mediated Copper Overload

Acetaminophen is commonly used as an antipyretic agent, but it is becoming one main cause of drug-induced liver injury (DILI) on overdose. Cuproptosis is a whole new cell death pathway induced by copper overload, characterized by proteotoxic stress due to lipoylated protein aggregation and iron-sulfur cluster protein loss. However, the role of cuproptosis in DILI and its underlying mechanism remains unclear. In this study, liver cuproptosis was found to be induced in DILI, presented by decreased levels of key suppressive molecules of cuproptosis [ferredoxin (FDX1), lipoyl synthase, and dihydrolipoamide S-acetyltransferase (DLAT)], along with copper overload. Furthermore, FDX1 knockdown led to induction of cuproptosis and aggregated liver injury in both mice and cells. Cuproptosis and liver injury can be reversed by copper deprivation via low-copper diet, whereas they can be exacerbated by high-copper diet. Moreover, oxidative stress relief, by glutathione supplementation and especially Nrf2 activation, resolved cuproptosis and decreased copper accumulation, and then reversed DILI. The above study reported that cuproptosis is induced in DILI by oxidative stress-induced copper accumulation. This research provided new clues to DILI treatment through cuproptosis inhibition, especially by Nrf2 activation-mediated oxidative stress relief, which would be a promising antidote in DILI.