Background: Annona squamosa L. (custard apple) seed extract contains bioactive acetogenins with known anticancer potential. Zinc oxide nanoparticles (ZnO NPs) demonstrate selective cytotoxicity toward tumor cells via reactive oxygen species generation. This study evaluated a green-synthesized A. squamosa/ZnO nanocomposite for its effects on hematological, biochemical, and histopathological parameters in a male mouse cancer model. Methods: In this study, a nanocomposite was synthesized by combining methanolic extract of A. squamosa seeds with zinc nitrate, and its properties were confirmed using UV–Vis spectroscopy, FESEM, AFM, EDS, XRD, and FTIR. One hundred male Swiss albino mice (8–12 weeks old) received weekly intraperitoneal injections for two months. Five groups were induced with cancer, of which four were co-treated with different doses of the nanocomposite (40, 80, 120, 200 mg/kg), and one served as a cancer control. The remaining five groups received the same nanocomposite doses without carcinogen. At the end of the study, blood samples were collected for complete blood count, liver enzymes, kidney markers, total protein, and electrolyte analysis. Liver and kidney tissues were examined histologically for pathological evaluation. Results: Cancer-only mice exhibited significant weight loss and elevated liver enzymes and renal markers versus healthy controls. In contrast, nanocomposite-treated mice demonstrated dose-dependent maintenance of body weight, normalization of liver enzyme activity and renal function parameters, and increased total protein levels. Electrolyte analysis revealed significant modulation of potassium and chloride concentrations, whereas sodium and calcium remained unchanged. Histopathological evaluation showed marked attenuation of hepatic necrosis, inflammatory infiltration, and renal tubular degeneration in treated mice compared to the cancer control. Conclusion: These findings indicate that A. squamosa/ZnO nanocomposite confers protective and corrective effects on liver and kidney function in a murine cancer model and support further investigation into its potential as a safe adjunct in anticancer therapy.
