Modulating regulated cell death: mechanistic insights into traditional Chinese medicine metabolites for ischemia/reperfusion-induced acute kidney injury.

Acute kidney injury (AKI), characterized by a rapid decline in renal function, represents a significant global health burden due to its high mortality and frequent progression to chronic kidney disease (CKD). Ischemia/reperfusion (I/R) injury is a major cause of AKI, yet clinically effective pharmacotherapies remain elusive. The pathogenesis of I/R-AKI is critically driven by regulated cell death (RCD) pathways-including apoptosis, ferroptosis, pyroptosis, and necroptosis-which mediate tubular epithelial damage and inflammatory responses. Consequently, targeting these RCD pathways emerges as a promising therapeutic strategy. Certain bioactive metabolites found in medicinal plants, including those used in traditional Chinese medicine (TCM), have demonstrated considerable potential in alleviating renal I/R injury. This review provides a detailed analysis of the mechanistic roles of key RCD pathways in I/R-AKI. Furthermore, it synthesizes preclinical evidence over recent decades to illustrate how specific TCM metabolites (e.g., hydroxysafflor yellow A, silibinin, salvianolic acid B, and gypenoside XLIX) confer renoprotection by modulating these RCD processes. To our knowledge, this work is the first to integrate the four major RCD pathways with a spectrum of TCM metabolites that modulate these processes in I/R-AKI. By presenting this integrated perspective, our review highlights TCM as a valuable repository for promising modulators of RCD pathways in I/R-AKI and outlines key priorities for future translational research.