Mangiferin mitigates mercuric chloride-induced hepatotoxicity: targeting Nrf2, NF-κB, NLRP3, and ER stress

Mangiferin (Man), a xanthone glucoside, has been reported for its antioxidant, antiviral, anticancer, anti-inflammatory, and gene-regulatory properties. Mercuric chloride (HgCl₂) is a toxic inorganic heavy metal compound that induces significant hematotoxic, hepatotoxic, neurotoxic, nephrotoxic, and genotoxic effects in biological systems. Therapeutic strategies targeting HgCl₂-induced liver damage remain inadequately investigated. This study evaluated Man's protective effect against HgCl₂-induced acute liver injury and the possible molecular mechanisms of hepatic protection effects in mice. Adult male BALB/c mice were administered two doses of Man (50 and 100 mg/kg, PO) 2 h before daily injections of HgCl₂ (3 mg/kg, IP) for seven consecutive days. The results indicated Man's protective capabilities, as shown by marked improvement in hepatic histological abnormalities caused by HgCl₂, along with the normalization of blood liver enzyme levels (ALT, AST, and LDH). These protective effects can be attributed to (i) cellular oxidative balance restoration via Nrf2 activation, TAC recovery, and NO and MDA reduction; (ii) suppression of pro-inflammatory signaling (NF-κB, NLRP3, IL-1β, and Casp-1); (iii) apoptotic-proliferative homeostasis restoration via Bax downregulation and Bcl-2 upregulation; and (iv) endoplasmic reticulum stress attenuation (PERK and CHOP). In conclusion, Man could be considered as a potential protective agent against HgCl₂-induced liver injury through controlling oxidative stress, inflammation, and apoptosis.