Pomegranate Extracts as Dual Regulators of Angiogenesis: A Systematic Review of Preclinical Evidence in Cancer and Chronic Wound Healing

Angiogenesis plays a critical role in both tumor progression and wound healing. This systematic review investigates the effect of pomegranate (Punica granatum, PG) extracts as both anti- and pro-angiogenic agents in preclinical models of cancer and chronic wound healing (CWH), respectively. Following PRISMA guidelines, 14 studies (10 cancer, 4 CWH) were identified from PubMed, Scopus, and Google Scholar databases. In cancer models, PG extracts (juice, peel extract, seed oil) reduced vascular endothelial growth factor (VEGF) expression, and endothelial tube formation across multiple cancer types, with concomitant decrease in matrix metalloproteinases and inflammatory mediators. Conversely, in CWH models, topical PG peel extract applications enhanced VEGF expression and wound closure in diabetic and burn injuries. This dual angiogenic effect appears mechanistically linked to peroxisome proliferator-activated receptor signaling pathways and synergistic interactions among PG polyphenols, particularly ellagitannins. Assessment of study quality revealed generally low risk of bias across in vitro studies, while animal studies demonstrated variable methodological rigor. Despite promising preclinical evidence, standardization of extraction methods, exploration of molecular mechanisms, and translation to clinical investigations remain critical research priorities. This comprehensive analysis validates PG extracts as a promising therapeutic strategy for both inhibiting pathological angiogenesis in cancer and promoting beneficial angiogenesis in CWH.