Dexpanthenol Attenuates Methotrexate-Induced Nephrotoxicity Through Modulation of NF-κB-Mediated Inflammation and SIRT1/PGC-1α-NRF2/HO-1-Associated Oxidative Stress Pathways.

Abstract

Methotrexate (MTX)-induced nephrotoxicity remains a clinically relevant limitation associated with oxidative stress, inflammation, and apoptosis. Dexpanthenol (DEX), a pantothenic acid derivative, has demonstrated cytoprotective properties; however, its effects on MTX-induced renal injury and related molecular pathways are not fully elucidated. This study investigated the potential renoprotective effects of DEX with a focus on inflammation- and redox-associated signaling. Thirty-two male Wistar rats were allocated into four groups: Control, MTX, MTX + DEX, and DEX. Renal injury was assessed by histopathology, immunohistochemical analysis of caspase-3, NF-κB, and TNF-α, biochemical parameters (urea and creatinine), and RT-qPCR analysis of SIRT1, PGC-1α, NRF2, and HO-1 gene expression. MTX administration resulted in marked renal damage characterized by tubular degeneration, hyperemia, and inflammatory infiltration, accompanied by increased caspase-3, NF-κB, and TNF-α expression (p < 0.001). MTX also significantly suppressed SIRT1, PGC-1α, NRF2, and HO-1 gene expression (p < 0.001). DEX co-treatment attenuated histopathological injury and significantly reduced pro-inflammatory and apoptotic markers while restoring SIRT1, PGC-1α, and HO-1 expression (p < 0.01-0.001), with a non-significant upward trend in NRF2 levels. Biochemically, DEX reduced MTX-induced urea and creatinine elevation. DEX confers significant protection against MTX-induced renal injury, likely through modulation of inflammatory and oxidative stress-related regulatory pathways and attenuation of apoptosis. These findings support the potential of DEX as a pharmacological candidate for mitigating drug-induced nephrotoxicity; however, further studies at the protein and functional levels are warranted.