Salidroside Alleviates Renal Ischemia-reperfusion Injury by Inhibiting Macrophage Pyroptosis Through HIF Signaling.

Renal ischemia-reperfusion injury (RIRI) is a critical pathological process characterized by hypoxia-driven inflammation and cell death. This study investigates the renoprotective effects of salidroside (Sa), a bioactive compound from Rhodiola rosea, in a murine RIRI model, focusing on its regulation of the HIF-1α-pyroptosis axis in macrophages. Through integrative approaches combining in vivo experiments, multiomics analysis, and functional assays, we demonstrated that Sa administration significantly attenuated renal dysfunction and tubular necrosis in RIRI mice. Mechanistically, Sa suppressed hypoxia-reoxygenation-induced HIF-1α stabilization in macrophages by quenching intracellular ROS, thereby disrupting the ROS-HIF-1α positive feedback loop. This inhibition led to reduced activation of the NLRP3 inflammasome, cleavage of gasdermin D (GSDMD), and secretion of pro-inflammatory cytokines (IL-1β/IL-18), ultimately mitigating macrophage pyroptosis. Single-cell RNA sequencing and network pharmacology further corroborated HIF-1 signaling as a central hub for Sa's action, with downregulation of pyroptosis-related genes in renal macrophages. Our findings establish Sa as a multi-target agent that alleviates RIRI by targeting the HIF-1α-driven pyroptotic cascade, offering a promising therapeutic strategy for ischemic kidney injury. Further studies are warranted to validate its clinical potential and molecular specificity.