Methotrexate-Induced Hepatotoxicity: A Narrative Review of Mechanisms, Risk Factors, and Management Strategies

Methotrexate (MTX) is a cornerstone agent in the treatment of inflammatory rheumatic diseases and acute lymphoblastic leukemia; however, its use is limited by concerns regarding hepatotoxicity. The high prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD) in the adult population (30–40%) makes it imperative to reassess the hepatic safety profile of MTX in this context. This study aims to synthesize current evidence on MTX-induced hepatotoxicity, addressing its mechanisms, risk factors, monitoring strategies, and potential therapeutic interventions. This is a narrative review based on the analysis of relevant studies published in scientific databases, focusing on recent advances concerning the interaction between MTX and MASLD, pharmacogenomics, noninvasive methods of liver assessment, and emerging therapeutic approaches. The presence of MASLD increases susceptibility to MTX-induced hepatotoxicity, and MTX may also accelerate the progression of underlying liver disease. Interindividual variability in toxicity is associated with genetic polymorphisms, notably in the TPMT and NUDT15 genes. Risk stratification can be effectively performed using noninvasive methods such as the Fibrosis-4 index and transient elastography. In high-dose settings, the use of glucarpidase has shown benefits, improving renal recovery (adjusted odds ratio 2.70) and reducing the incidence of severe transaminitis (adjusted odds ratio 0.50). Studies using hepatic organoids confirm the fibrogenic potential of MTX and suggest the possibility of antifibrotic agents as therapeutic alternatives. The recognition of MASLD as a modifiable risk factor and the implementation of pharmacogenomics-guided dosing strategies represent crucial advances in mitigating MTX-induced liver injury, optimizing its safety and efficacy in clinical practice.