Work

CuSO4 protects hepatocytes from lipotoxicity by promoting autophagic degradation of lipid droplets to attenuate oxidative stress

Year: 2025

Type: article

Abstract: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent chronic liver condition that often progresses to Metabolic Dysfunction-Associated Steatohepatitis (MASH), ultimately leading to liver fibrosis and hepatocellular carcinoma (HCC). Consequently, the early diagnosis and treatment of MASLD are particularly crucial. Currently, the pathogenic mechanisms underlying MASLD remain incompletely understood, and there is no optimal therapy available for this condition. The liver serves as the primary organ for copper storage, maintaining copper levels within a stable range under physiological conditions. Both copper deficiency and excess can result in cellular damage and liver dysfunction. In this study, we demonstrate that hepatic copper deficiency is closely associated with the pathogenesis of MASLD. Furthermore, we found that CuSO 4 influence the progression of MASLD by modulating the Chaperone-Mediated Autophagy (CMA) pathway, thereby restoring the autophagic degradation of lipid droplets, reducing oxidative stress, enhancing cell viability, and alleviating lipid deposition. In summary, by investigating the potential relationship between intrahepatic copper deficiency and MASLD, we have explored the protective role of copper ions in hepatocytes and laid the groundwork for developing molecular markers for diagnosing and treating MASLD. In hepatocytes undergoing lipotoxic injury, intracellular lipid droplets accumulate, and the increase of copper ions could protect hepatocytes from lipotoxicity. Copper ions can restore the autophagy degradation of lipid droplets by regulating the CMA pathway, reduce oxidative stress, improve cell viability and relieve lipid deposition, thus affecting the development of MASLD. • Serum copper concentration is negatively correlated with MASLD. • CuSO 4 effectively inhibits lipid deposition in MASLD. • CuSO 4 mitigates oxidative stress, enhances hepatocyte viability, and reduces apoptosis in lipotoxic hepatocytes. • CuSO 4 reduces lipid accumulation by enhancing lipid droplet autophagy.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.118848

Authors: Wei Xie, Yu Zhang, Feng Sun, Wei Luo, Yongmin Yan, Jing Zhou