Ginsenoside Rb1-Engineered Nanocomposite Hydrogel Promotes Pressure Injury Repair through SIRT1-AMPK-Mediated Ferroptosis Inhibition and Angiogenesis Activation

Background Pressure injuries (PIs) remain a therapeutic challenge due to persistent inflammation and ferroptosis-driven tissue damage. Ginsenoside Rb1, a key bioactive component of Panax ginseng, demonstrates anti-inflammatory and anti-ferroptotic properties, but its clinical application is limited by poor bioavailability and rapid degradation in wound environments. Purpose This study aimed to develop a chitosan/alginate nanocomposite hydrogel loaded with ginsenoside Rb1 (Rb1@CS@ALG) to enhance Rb1 delivery and investigate its therapeutic mechanisms in PI repair, focusing on SIRT1-AMPK-mediated ferroptosis inhibition and angiogenesis promotion. Methods The pH-responsive Rb1@CS@ALG hydrogel was synthesized and characterized (TEM/DLS/HPLC). In vitro studies evaluated ferroptosis markers (GPX4, SLC7A11), ROS levels, and cell migration in HaCaT cells under ischemia-reperfusion. A rat PI model (n=6/group) assessed wound closure rates, histopathology (H&E/Masson's), and protein expression (CD31/Col I). RNA-seq analyzed differential gene expression. Results The hydrogel showed sustained Rb1 release (82.3% at 24 h) and pH-dependent drug delivery. Treatment upregulated GPX4/SLC7A11 (2.3-fold) while reducing ROS (58%) and ACSL4 (45%) via SIRT1-AMPK activation (p-AMPK↑2.9-fold). In vivo, it accelerated wound closure by 75% (vs. controls, p<0.001), increased angiogenesis (CD31↑3.1-fold), and improved collagen organization (Col I/III ratio↑2.7-fold). RNA-seq confirmed enrichment in ferroptosis and extracellular matrix pathways. Conclusion This study establishes ginsenoside Rb1 as a potent therapeutic agent for PIs when delivered via nanocomposite hydrogel, with dual mechanisms of ferroptosis inhibition and angiogenesis activation. The findings provide a scientific foundation for applying ginseng-derived compounds in chronic wound management.