Modulation of SIRT-1, NF-κB/TNF-α/IL-6, and ERK/Caspase-3 by Lutein Mitigates Methotrexate-Induced Hepatotoxicity

<b>Background/Objectives</b>: Methotrexate (MTX) is an effective immunosuppressant and chemotherapeutic agent used to manage various cancers and inflammatory illnesses, but its hepatotoxic hazards pose a major challenge to its clinical application. The preventive influence of lutein against MTX-elicited liver damage was assessed in the present study, focusing on its impact on the SIRT-1, NF-κB -TNF-α-IL-6, and ERK-caspase-3 signaling pathways. <b>Methods</b>: Forty male Wistar rats were randomly assigned into control, Lutein 100 mg, MTX, MTX + Lutein 50 mg, and MTX + Lutein 100 mg groups. MTX groups were intraperitoneally injected with MTX (40 mg/kg) on day 7, while lutein was daily administered by oral route for 10 days. <b>Results</b>: MTX-induced liver damage was evident by significant structural damage and elevation in hepatic biochemical markers. MTX intoxication induced disturbance in the oxidant/antioxidant equilibrium, downregulated SIRT-1, inflammation reflected by upregulation of pro-inflammatory cytokines, NF-κB, eventual TNF-α and IL-6 levels, and apoptosis evident by elevated ERK-caspase-3 in hepatic tissue. Notably, pre-conditioning with lutein mitigated these harmful effects. Lutein's therapeutic impact is mechanistically explained by its antioxidant potential, in addition to its ability to enhance SIRT-1 expression and abrogate the inflammatory NF-κB -TNF-α-IL-6 pathway and apoptotic ERK-caspase-3 response. <b>Conclusions</b>: Overall, these outcomes suggest that lutein could be applied as a promising therapeutic tool to be combined with MTX to attenuate the risk of its hepatotoxicity.