[Role of glutathione in regulating ferroptosis and cuproptosis in metabolic dysfunction-associated steatotic liver disease].

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a fatty liver disease characterized by metabolic dysfunction as its core feature. It represents one of the most common causes of liver disease worldwide and imposes a substantial disease burden. Abnormal cell death patterns are involved in the initiation and progression of MASLD, and ferroptosis and cuproptosis have recently emerged as research hotspots due to their roles in triggering and exacerbating MASLD. Glutathione (GSH), the most important reductant in redox regulation, can promote hepatic lipid accumulation and oxidative injury when its levels decline or become depleted, thereby driving the progression of MASLD. GSH serves as a common hub linking ferroptosis and cuproptosis: on the one hand, GSH acts as an essential reducing substrate for glutathione peroxidase 4 (GPX4) and suppresses ferroptosis by eliminating toxic lipid peroxides; On the other hand, GSH chelates excessive intracellular cuprous ions (Cu⁺), reducing the cytotoxicity of Cu⁺ and thus inhibiting cuproptosis. Therefore, GSH is a key regulator of ferroptosis and cuproptosis in MASLD, and targeting the GSH metabolic pathway holds promise as a potential novel strategy for the prevention, diagnosis, and treatment of MASLD. Future investigations should focus on dissecting the molecular network of GSH‑mediated crosstalk between ferroptosis and cuproptosis and integrating advanced approaches such as nano‑targeted delivery and gene editing to develop safe and potent GSH‑directed modulators, thereby expediting the translation of basic research findings into clinical practice.