Mechanistic Evaluation of Chlorfenapyr‐Induced Hepatotoxicity and the Mitigating Actions of Resveratrol‐Loaded Chitosan Nanoparticles

Chlorfenapyr (CFP) is an insecticide known to induce hepatotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. Resveratrol (RES) exhibits antioxidant and anti-inflammatory properties, and its delivery via chitosan nanoparticles (RES-CNPs) may enhance its protective effects. This study aimed to investigate the hepatoprotective potential of RES and RES-CNPs against CFP-induced liver damage in Wistar rats. Sixty male Wistar rats were randomly divided into six groups (n = 10): control, RES, RES-CNPs, CFP, CFP + RES, and CFP + RES-CNPs. Treatments were administered orally for 30 days. Liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, inflammatory gene expression, histopathology, and ultrastructure were evaluated exposure significantly decreased total protein, albumin, antioxidant levels (GSH, CAT, SOD, GPX), ATP, and PDH activity, while increasing liver enzymes (AST, ALT, ALP), lipid peroxidation (MDA, PCO), mitochondrial dysfunction, inflammatory gene expression (NF-κB, TNF-α, IL-6), CRP, and total leukocyte count (p < 0.05). Co-administration of RES-CNPs significantly restored these biochemical, molecular, and histological parameters, showing superior efficacy to crude RES in most endpoints and achieving values close to the negative control for several markers (p > 0.05). Histopathological and ultrastructural analyses confirmed CFP-induced hepatocyte degeneration and necrosis, which were ameliorated by RES-CNPs, with near-normal liver architecture and cellular integrity. RES-CNPs effectively mitigate CFP-induced hepatotoxicity by restoring liver function, enhancing antioxidant defenses, preserving mitochondrial function, and suppressing inflammation. RES-CNPs demonstrated superior hepatoprotective effects compared to crude RES, highlighting their potential as a therapeutic strategy against xenobiotic-induced liver injury.