The mechanism of CISD3 regulating NRF2-ATP7B to ameliorate alcohol-induced liver mitochondrial dysfunction and cuproptosis.

Globally prevalent alcoholic liver disease (ALD) stands as a predominant form of persistent hepatic pathology, which has emerged as a critical public health challenge given its progressively worsening epidemiological trends. Recent studies have identified CDGSH iron‑sulfur domain-containing protein 3 (CISD3) as a key regulator of mitochondrial function. Although its role in non-alcoholic liver diseases and autoimmune liver diseases has been established, its specific mechanism in ALD remains unclear.In this study, we established both in vivo and in vitro ALD models and, for the first time, observed downregulation of CISD3 expression in ALD hepatocytes, accompanied by significant mitochondrial dysfunction and cuproptosis. Further investigations demonstrated that CISD3 knockout exacerbated lipid accumulation in ALD while aggravating mitochondrial dysfunction and copper metabolism dysregulation, whereas CISD3 overexpression effectively ameliorated these pathological alterations. Mechanistic studies revealed that CISD3 likely mitigates ALD progression potentially through the Nuclear factor erythroid 2-related factor 2(NRF2)/ATPase copper transporting beta(ATP7B) signaling network activation.These significant findings not only elucidate the critical role of CISD3 in ALD pathogenesis and its underlying molecular mechanisms but, more importantly, suggest that CISD3 may serve as a potential novel therapeutic target for ALD, providing new theoretical foundations and treatment strategies for clinical intervention.