Pharmacological Mechanisms of Phytochemicals and Pharmaceutical Agents in Protecting Against Methotrexate‐Induced Liver Injury

Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent for treating various malignancies, autoimmune diseases (AIDs), and inflammatory disorders. Despite its therapeutic efficacy, long term or high-dose MTX treatment is associated with a significant risk of hepatotoxicity, leading to MTX-induced liver injury (MTX-LI). The pathogenesis of MTX-LI involves multiple mechanisms, including oxidative stress, mitochondrial dysfunction, inflammation, and altered metabolic processes, which collectively contribute to hepatocellular damage and fibrosis. Clinically, MTX-LI manifests as elevated liver enzymes, hepatic steatosis, and, in severe cases, cirrhosis, posing a challenge to treatment regimens. To mitigate MTX-LI, a growing body of research has focused on exploring therapeutic and/or preventive potential and pharmacological mechanisms of phytochemicals and pharmaceuticals. Phytochemicals, including flavonoids, terpenoids, alkaloids, and polyphenols, exhibit hepatoprotective effects attributed to their antioxidant, anti-inflammatory, and antiapoptotic properties that can counteract MTX-induced hepatic damage. Additionally, various pharmaceutical agents possessing antioxidants and anti-inflammatory properties and favorably modulate metabolic pathways have shown promise in reducing the severity or progression of of MTX-LI. The phytochemicals or pharmaceuticals showed beneficial in MTX-LI primarily act by scavenging reactive oxygen species (ROS), modulating inflammatory pathways, and improving liver regeneration. Integrated together, its apparent that naturally occurring many phytochemicals as well as synthetic agents of pharmaceutical relevance are capable of preventing or alleviating MTX-LI. However, the optimal strategies for integrating these agents into clinical practice require further investigations to highlight safety and efficacy in humans followed by pharmacological rationale of their possible use in therapeutics. Future directions should focus on elucidating the precise molecular mechanisms, establish safety and efficacy in humans, conducting regulatory toxicology studies and randomized clinical trials, and developing combination therapies for promotion as protective agents or adjuvants to maximize efficacy and minimize adverse effects.