Hylocereus undatus peel extract and ZnO nanoparticles suppress cancer through apoptosis and Wnt/β-catenin inhibition

Cancer treatment faces the challenge of multidrug resistance and systemic cytotoxicity. This study explores the anticancer potential of Hylocereus undatus peel extracts and their biogenically synthesized zinc oxide nanoparticles (ZnO NPs). Total phenolics, flavonoids and GC–MS profiles of the extracts were determined. Then, ZnO NPs were synthesized by using aqueous and n-hexane extracts and characterized by FTIR, Zeta Potential, XRD, SEM, EDX, and TEM. Among all tested formulations, ZnO NPs-AE (derived from the aqueous extract) showed the strongest antitumor activity, both in cell culture (Caco‑2 and HepG2) and in the Ehrlich ascites carcinoma mouse model. In MTT assays, ZnO NPs-AE was highly cytotoxic to Caco‑2 and HepG2 cells (IC₅₀ = 9.22 and 12.93 µg/mL, respectively) and performed on the same level as doxorubicin ( p < 0.05). It also showed a more favourable selectivity profile, being less toxic to normal colon fibroblasts (CCD‑18Co; IC₅₀ = 32.35 µg/mL) than to Caco‑2 cells (IC₅₀ = 9.22 µg/mL), which was better than doxorubicin. Consistent with this, ZnO NPs-AE reduced the proportion of cells in G2/M phase (7.39% compared with 12.65% in untreated cells) and increased total apoptosis to 25.98% in Caco‑2 cells. Molecularly, it up-regulated caspase-3 (6.15-fold), down-regulated topoisomerase II (0.33-fold) and suppressed the Wnt/β catenin axis. Consistently, ELISA quantification of Axin2 and Cyclin D1 in Caco‑2 cells confirmed down‑regulation of these Wnt/β‑catenin targets in parallel with the decrease in β‑catenin protein. In vivo, ZnO NPs-AE (5 mg/kg) reduced EAC volume to 89.36%, normalized hepatic/renal biomarkers, improved lipid profiles, and alleviated oxidative stress by elevating GSH, CAT, and SOD levels, while reducing MDA, alongside histopathological improvements. Overall, ZnO NPs-AE represents a promising, well tolerated biogenic nanoplatform for targeted cancer therapy.