Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Punica granatum (pomegranate) peel is traditionally used for its antimicrobial and health-promoting properties in several cultures. Rich in polyphenols, the peel has attracted interest for its potential applications in treating infections and cancer, particularly in integrative approaches for immunocompromised patients. MATERIALS AND METHODS: Pomegranate peel extracts were prepared using solvents of increasing polarity, with emphasis on the ethyl acetate fraction (PPE-EA). A nano-formulated version (n-PPE-EA) was developed using a standard nano-encapsulation technique. Cytotoxic activity was evaluated in THP-1 human leukemia cells using MTT assay, flow cytometry, and biochemical analyses. Antimicrobial activity was assessed against Streptococcus pyogenes via agar diffusion. Gene expression of BCL2, PI3K, and CDK8 was measured to elucidate mechanisms of action. RESULTS: Among all tested extracts, PPE-EA showed the strongest dual activity, reducing THP-1 cell viability by over 50% at 100 µg/mL and inhibiting S. pyogenes with a 10.5 ± 1.1 mm zone. Nano-encapsulation enhanced both effects, reducing the IC₅₀ from 1.48 ± 0.03 µg/mL to 0.19 ± 0.01 µg/mL and increasing the bacterial inhibition zone to 15.6 ± 0.5 mm. n-PPE-EA induced apoptosis, cell cycle arrest, elevated catalase activity, and reduced malondialdehyde levels. It also downregulated BCL2, PI3K, and CDK8 expression. CONCLUSION: The nano-formulated PPE-EA demonstrated potent cytotoxic and antimicrobial activities, with enhanced efficacy attributed to improved bioavailability and modulation of apoptotic and cell cycle pathways. These findings support its potential as a multifunctional therapeutic agent in integrative cancer care. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-026-05291-9.