Isoliquiritigenin, Nrf2 Activator, and NLRP3 Inhibitor Protects Isoniazid‐Induced Hepatotoxicity in Sprague‐Dawley Rats: Studies on Oxidative Stress, Inflammation, DNA Damage, Ferroptosis, and Steatosis

Isoniazid (INH), a widely used first-line anti-tubercular drug, has significant concern for the hepatotoxicity in humans induced by oxidative stress, inflammation and steatosis. INH activates NLRP3 inflammasome and inhibits Nrf2 activation pathways. Isoliquiritigenin (ISO), a bioactive flavonoid, possesses antioxidant and anti-inflammatory characteristics and responsible for the hepatoprotection in several experimental models. Male SD rats were assigned into six groups: control, ISO per se (20 mg/kg, p.o.), INH (50 mg/kg, p.o.), INH + ISO- low dose (5 mg/kg, p.o.), mid dose (10 mg/kg, p.o.), and high dose (20 mg/kg, p.o.). Hepatotoxicity was evaluated using different parameters such as SGPT, SGOT, ALP, GGT, bilirubin, oxidative stress such as MDA, CAT, GSH, inflammation by evaluating NLRP3 expression, fibrosis by measuring collagen deposition as well as histological assessment. INH treatment significantly perturbed the liver enzymes, oxidative stress indicators, while decreased the endogenous antioxidants. Histopathological examination confirmed liver damage, which included inflammation, steatosis, and fibrosis. ISO co-administration significantly reduced these changes by restoring the antioxidant defense mechanisms, decreasing inflammatory mediators, and suppressing fibrotic changes. ISO significantly reduced INH-induced hepatotoxicity by regulating the oxidative stress, inflammation, and steatosis pathways. Based on the mechanism of Nrf2 activation and NLRP3 inhibition, the present results provide the evidence that ISO has the potential to restore the liver damage and can act as a novel therapeutic strategy for INH induced hepatotoxicity in humans.