Plant-derived phytochemicals are promising therapeutic agents against heavy metal–induced toxicity. This study evaluated the protective efficacy of Carica papaya (CP) leaf and Ziziphus mauritiana (ZM) fruit pulp ethanolic (70%) extracts against cadmium (Cd)-induced hepatorenal toxicity in rats. Fifty-six male Wistar rats (n=7) were divided into eight groups and treated for four weeks. CdCl₂ (5 mg/kg/day) was administered orally, whereas CP and ZM extracts were given (separately) (300 mg/kg/day) or in combination (150 mg/kg each). Hepatic, renal, lipid, and hematological parameters, along with antioxidant, oxidative stress, inflammatory, apoptotic, and anti-apoptotic gene expression profiles, were assessed to determine the therapeutic potential of both extracts. Molecular docking, comet assay, and histopathological analyses were also performed. Data were analyzed using one-way ANOVA followed by Dunnett’s test (GraphPad Prism, P<0.05). Cd exposure caused significant hepatorenal dysfunction, dyslipidemia, and hematological alterations, accompanied by elevated ALT, AST, ALP, GGT, bilirubin, urea, serum creatinine, BUN, NGAL, KIM-1, and Semaphorin-3A. Cd also suppressed antioxidant enzymes (SOD, CAT, GPx, GR, and GSH) and significantly increased oxidative stress, inflammatory mediators, and pro-apoptotic gene expression, while reducing anti-apoptotic markers. Supplementation with CP and ZM extracts, particularly in combination, markedly improved hepatorenal, hematological, and lipid profiles, restored antioxidant defenses and mitigated oxidative damage. Treated groups showed reduced DNA tail length and intensity in comet assay, indicating genoprotection. Histopathology revealed preserved hepatic and renal morphology with minimal necrosis and inflammation. Molecular docking demonstrated strong binding affinities of key phytochemicals with NF-κB and 2AZ5, suggesting potential molecular mechanisms underlying the observed protective effects. Conclusively, CP and ZM showed synergistic therapeutic efficacy against Cd toxicity.

To Cite This Article: Hussain S, Rafique A, Ashraf A and Asad F, 2026. Mitigation of Cadmium-induced hepatorenal toxicity in male Wistar rats using Carica papaya and Ziziphus mauritiana. Pak Vet J, 46(4): 790-805. http://dx.doi.org/10.29261/pakvetj/2026.079