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

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. This study aimed to investigate the potential hepatoprotective effects of L-carnitine (LCR), a mitochondrial cofactor with antioxidant and anti-apoptotic properties, in a rat model of MTX-induced hepatotoxicity. 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. MTX administration induced histological injury, upregulated CD38 and GLUT1 expression and altered apoptosis-related genes (BAX↑, BCL2↓) with a trend toward elevated ALT and AST levels. LCR co-treatment improved hepatic histoarchitecture, reduced CD38 and GLUT1 expression and partially normalized BAX/BCL2 expression, with a tendency to restore serum enzyme activity. L-carnitine may attenuate MTX-induced hepatotoxicity by modulating oxidative stress, metabolic stress and apoptotic signaling. These findings suggest a potential role for L-carnitine as an adjuvant to improve hepatic safety during MTX therapy.