Artocarpin alleviates fenofibrate-induced hepatic dysfunction via regulating NLRP3/caspase-1, oxidative stress and bile acids synthesis: A biochemical, histological, and computational investigation

ABSTRACT

Fenofibrate (FBR) is a promising hypolipidemic drug that is reported to induce hepatic impairments. Artocarpin (ACP) is a novel polyphenolic compound with diverse biological properties. This investigation was planned to explore the palliative efficacy of ACP in combating FBR-induced hepatotoxicity. Thirty-two Sprague Dawley rats were grouped into control, FBR (100 mg/kg), FBR (100 mg/kg) + ACP (100 mg/kg), and ACP (100 mg/kg) alone administered group. Our findings showed that FBR intoxication upregulated the mRNA expressions of CXCR4, CCR5, Caspase-1, IL-1β, CCL2, IL-18 and NLRP3. The levels of ROS and MDA were augmented while the enzymatic action of GST, HO-1, SOD, GPx, GSR, GST, and CAT were suppressed following the exposure of FBR. Besides, FBR intoxication induced cholestatic stress as evidenced by elevated levels of chenodeoxycholic, deoxycholic acid, cholic acid, glycocholic acid and taurocholic acid. The levels of ALP, GGT, AST, hepcidin, and ALT were aggravated while the levels of total protein, hemojuvelin, and albumin were inhibited by FBR administration. Moreover, FBR exposure compromised the morphology of liver by altering key structural components. Importantly, concurrent therapy of ACP restored hepatic health by inhibiting the activation of NLRP3/Caspase-1 pathway, reducing hepatic enzymes, oxidative stress while regulating iron metabolism as well as bile acid metabolic alterations. Furthermore, ACP reversed histological alterations in hepatic tissues. These findings are supported by our in-silico analysis which exhibits excellent modulatory activity of ACP by binding at key regulatory binding sites. Collectively, these results underscore the hepatoprotective efficacy of ACP against FBR-induced liver impairments.