Integrated network pharmacology, transcriptomics, and molecular simulations reveal polydatin protects against aortic dissection associated with PPARγ/Nrf2-related antioxidant signaling

Integrative computational analyses identify PPARG as a key target of polydatin in aortic dissection. • Docking and MD support stable binding of polydatin to PPARγ and Keap1. • Transcriptomic and WGCNA analyses link polydatin to oxidative-stress regulation. • Polydatin attenuates BAPN-induced aortic dissection in mice. • Polydatin may protect the aortic wall via the PPARγ/Nrf2 antioxidant axis. Aortic dissection (AD) is a life-threatening vascular disease characterized by medial degeneration, extracellular matrix (ECM) destruction, inflammation, and oxidative stress. Polydatin (PD), a natural stilbene glucoside, has cardiovascular protective potential, but its mechanism against AD remains unclear. This study investigated the therapeutic mechanism of PD in AD by integrating network pharmacology, transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), molecular modeling, and in vivo validation. IGF1, PPARG, and KDR were identified as core targets in the PD–AD network, with PPARG prioritized for its association with vascular redox homeostasis, inflammation, and antioxidant defense. Molecular docking and molecular dynamics simulations indicated stable interactions between PD and PPARγ and Keap1, a key regulator of Nrf2 stability. In a β-aminopropionitrile (BAPN)-induced AD mouse model, PD significantly reduced aortic dilation and medial injury, preserved elastic fiber architecture, and attenuated ECM degradation. PD also decreased ROS and MDA levels, restored SOD, GSH-Px, and CAT activities, and upregulated PPARγ, Nrf2, HO-1, and NQO1 expression. These findings suggest that PD alleviates AD by restoring vascular redox homeostasis, potentially involving PPARγ-associated signaling and Nrf2-related antioxidant responses, supporting PD as a potential therapeutic candidate for AD-related vascular degeneration. Download: Download high-res image (327KB) Download: Download full-size image