Mangiferin mitigates methotrexate-induced liver injury and suppresses hepatic stellate cells activation in rats: Imperative role of Nrf2/NF-κB/NLRP3 signaling axis

Ethnopharmacological relevance: Mangifera indica (family Anacardiaceae), often acknowledged as mango and renowned for being a plant of diverse ethnopharmacological background since ancient times, harbors the polyphenolic bioactive constituent, mangiferin (MNG). MNG is a major phytochemical of Mangifera indica and other plants with a wide range of reported pharmacological activities, including antioxidant, anti-inflammatory, neuroprotective and hepatoprotective effects. MNG has also been utilized in traditional medicine; it is reportedly a major bioactive element in over 40 polyherbal products in traditional Chinese medicine (TCM), and two prominent anti-inflammatory, immunomodulatory and antiviral Cuban formulations. Despite the availability of evidence in support of MNG hepatoprotective properties, its hepatoprotective potential against MTX-induced liver injury and fibrosis has not been explored yet.

Aim: To unravel the hepatoprotective potential of MNG against MTX-induced hepatic injury and fibrosis and elucidate the possible underlying molecular mechanisms.

Materials and methods: Male Sprague-Dawley rats were, randomly, distributed into five groups; two of which were administered MNG 50 mg/kg and MNG 100 mg/kg intraperitoneally (i.p.) for ten days, and a single i.p. injection of MTX 40 mg/kg on the seventh day to establish hepatotoxicity. Blood and liver tissue samples were retrieved from all study groups and analyzed for liver functions, histopathological alterations, and oxidative stress, inflammatory, and fibrotic biomarkers.

Results: MNG restored the MTX-induced degenerations in hepatic architecture and function. Moreover, it combated the MTX-elicited oxidative stress evidently by the significantly attenuated hepatic tissue levels of malondialdehyde, and the significantly elevated reduced glutathione and Nrf2 levels. MNG also halted inflammation depicted by the downregulation of the NF-κB/NLRP3 inflammasome axis. It further demonstrated anti-fibrogenic potential as evidenced by the significant reduction in fibrous tissue deposition and hepatic expression of α-SMA.

Conclusion: The current study proved the hepatoprotective, and anti-fibrogenic effects of MNG against MTX-induced hepatotoxicity via the downregulation of NF-κB/NLRP3 inflammasome signaling axis, preceded by the amelioration of oxidative stress and Nrf2 signaling upregulation.