Metallothioneins in the Pathogenesis of Liver Diseases: A Review

Metallothioneins (MTs) are primarily known for maintaining cellular metal homeostasis and protecting against metal toxicity, but they also play critical roles in mitigating oxidative stress and modulating immune responses. Reduced MTs expression is associated with disease progression in several chronic hepatic disorders. In metabolic dysfunction-associated steatotic liver disease (MASLD), MT1 downregulation has been linked to the transition from simple steatosis to steatohepatitis. Additionally, evidence suggests that individuals with low MTs expression may be more susceptible to obesity, which is one of the key drivers in the development of MASLD. In chronic viral hepatitis, in vivo MTs downregulation contrasts with acute-phase in vitro upregulation, suggesting an effect of persistent inflammation. MTs downregulation in hepatocellular carcinoma (HCC) correlates with poor prognosis, positioning MTs as potential biomarkers and therapeutic targets. In contrast, increased MTs expression may play a protective or diagnostically informative role in other conditions. In alcoholic hepatitis, MT1 overexpression contributes to defense against oxidative stress and inflammation. In Wilson's disease, MTs demonstrates prominent hepatic expression and may offer diagnostic value alongside traditional markers such as rhodanine staining. In cholestatic liver diseases like PBC and PSC, MTs expression correlates with disease progression. This review highlights the emerging role of MTs in liver disease pathogenesis and positions them as promising molecular tools that may inform future strategies for diagnosis, prognosis, and treatment of liver diseases.