L-Carnitine protects against methotrexate-induced hepatotoxicity via regulation of apoptosis and metabolic pathways

Background Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive drug; however, its clinical application is limited by dose-dependent hepatotoxicity mediated by oxidative stress, mitochondrial dysfunction, and apoptosis. Objective This study aimed to evaluate the hepatoprotective potential of L-carnitine (LCR), a mitochondrial cofactor with antioxidant and anti-apoptotic properties, in a rat model of MTX-induced hepatotoxicity. Methods Twenty-four male Wistar rats were randomly divided into four groups: Control, MTX (20 mg/kg, i.p., single dose), LCR (100 mg/kg/day, oral), and MTX + LCR. After 10 days, liver tissues were examined histopathologically, immunohistochemically for CD38 and GLUT1, and by qPCR for BAX and BCL2 expression. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were also measured. Results MTX administration elevated ALT and AST levels, caused histological injury, upregulated CD38 and GLUT1 expression, and dysregulated apoptosis-related genes (BAX↑, BCL2↓). LCR co-treatment improved hepatic histoarchitecture, reduced CD38 and GLUT1 expression, partially normalized BAX/BCL2 levels, and tended to restore serum enzyme activity. Conclusion L-carnitine protects against MTX-induced hepatotoxicity by reducing oxidative and metabolic stress and modulating apoptosis. These findings support the potential of L-carnitine as an adjuvant in MTX-based chemotherapy to enhance hepatic safety and minimize off-target toxicity.