Cardiovascular and cerebrovascular diseases, including coronary artery disease (CAD), myocardial infarction (MI), carotid atherosclerosis (CAS), and cerebral ischemic stroke (CIS), continue to impose a significant global health burden due to the limited therapeutic efficacy of current clinical interventions. Punicalagin (PU), a pomegranate-derived polyphenol with antioxidant and anti-inflammatory properties, exhibits therapeutic potential but requires mechanistic clarification.

This study employed integrated network pharmacology, molecular docking, and experimental validation to identify PU’s multi-target mechanisms.

PU has 519 potential targets and shares 185 common targets with CAD, MI, CAS, and CIS. Molecular docking analysis showed that PU had strong binding affinity with HIF-1α, CASPASE3 and TLR4 targets. Experimental validation using the OGD/R model in HT22 cells revealed that PU treatment significantly reduced reactive oxygen species (ROS) levels and apoptosis, while downregulating the expression of HIF-1α, CASPASE3 and TLR4. PU plays a critical role in cardiovascular and cerebrovascular diseases through the modulation of pathways associated with HIF-1α, CASPASE3 and TLR4.

Our study revealed the therapeutic effects and underlying mechanisms of PU on CAD, MI, CAS, and CIS, providing a foundation for subsequent in vivo and clinical studies on PU as a potential therapeutic agent.