Hepatocyte cuproptosis promotes the progression of hepatic fibrosis: Emerging a potential therapeutic target

Copper (Cu)-dependent aggregation of lipoylated proteins in mitochondria triggers cuproptosis, a newly discovered modality of regulated cell death marked by impaired mitochondrial respiration. During the progression of hepatic fibrosis (HF), hepatocytes, responsible for Cu storage and metabolism, exhibit vigorous mitochondrial activity and are supposed to be cuproptosis-susceptible. However, the cellular landscape of cuproptosis in fibrotic livers remains unclear, and the therapeutic potential of cuproptosis suppression in resolving HF has yet to be explored. In this study, single-cell RNA sequencing data from mouse models and clinical samples from HF patients show that hepatocytes are the dominant cell population attacked by cuproptosis. These cuproptotic hepatocytes release pro-fibrotic signals that activate hepatic stellate cells (HSCs), inducing the formation of fibrotic scar. Tannic acid (TA), a polyphenolic-molecule cuproptosis inhibitor, can combat the changes in cuproptotic hepatocytes stimulated by elesclomol plus Cu supplement in vitro, including intracellular Cu (I) concentration, mitochondrial membrane potential, and expression pattern of cuproptosis regulators. In addition, the production of pro-fibrotic signals is inhibited by TA, and subsequently the activation of HSCs. Finally, TA is demonstrated to prevent the progression of HF in mouse models, as evidenced by the improvement of liver architecture and function. Proteomic analysis reveals that the disturbed lipid metabolism and cuproptosis regulator expression in fibrotic livers are both rescued by TA. Collectively, these findings highlight hepatocyte cuproptosis as a key driver of the fibrotic process, and its suppression holds great therapeutic promise for treating HF.