Immunomodulation by Simvastatin: A Key Mechanism in Attenuating Methotrexate-Induced Kidney Injury Through NF-κB and Oxidative Stress

Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent known to induce renal toxicity through mechanisms involving oxidative stress, inflammation, and apoptosis. This study aimed to evaluate the renoprotective effects of SIM against MTX-induced nephrotoxicity in rats. Thirty-two male Sprague-Dawley rats were randomly divided into four groups: control, SIM, MTX, and MTX+SIM. MTX administration significantly elevated serum Cr and urea levels increased renal MDA, and suppressed antioxidant enzymes, including SOD, CAT, and GPx. It also upregulated inflammatory markers such as NF-κB, TNF-α, IL-6, and IL-1β, and triggered apoptosis via increased expression of p53, cytochrome c, Bax, and caspase-3. Co-treatment with SIM significantly mitigated these pathological changes, restoring renal function, enhancing antioxidant defenses, suppressing inflammation, and downregulating apoptotic proteins. These findings highlight the multi-targeted therapeutic potential of SIM in mitigating MTX-induced renal injury and preserving kidney integrity.