Ischemia-reperfusion injury is a leading cause of acute kidney injury (AKI), which is characterized by high morbidity and mortality, as well as a substantial risk of progression to chronic kidney disease (CKD). Although supportive care has improved considerably, effective disease-modifying therapies are still lacking. Therefore, the development of new therapeutic drugs for ischemic AKI is crucial. Active metabolites derived from medicinal plants, owing to their low toxicity and multi-target characteristics, are promising candidates for ischemic AKI therapy. This study reviews the pathogenesis of ischemic AKI from multiple dimensions, including metabolic disturbances, oxidative stress, inflammation, endoplasmic reticulum stress, mitochondrial dysfunction, and several forms of regulated cell death (e.g., ferroptosis, apoptosis, pyroptosis). It also summarizes plant metabolites (polyphenols, phenylpropanoids, terpenoids, saponins, alkaloids, and extracts) that can ameliorate ischemic AKI by targeting the aforementioned mechanisms. These metabolites exert their protective effects by modulating key signaling pathways (e.g., Nrf2/HO-1, NF-κB, PI3K/Akt). However, further mechanistic studies, standardization, and well-designed clinical trials are essential for their use and to ensure their integration into clinical practice as effective therapeutic options.

Introduction: Cisplatin (CIS)-induced nephrotoxicity is a dose-limiting adverse effect that hinders its clinical efficacy. Artesunate (ART) exerts well-documented anti-inflammatory and anti-oxidative effects, but its potential efficacy against CIS-induced nephrotoxicity remains poorly elucidated. Methods: The renoprotective effects of ART were evaluated in a murine CIS-induced nephrotoxicity model and human HK-2 renal tubular epithelial cells. Renal function, histopathological injury, inflammation, and oxidative stress were evaluated. Untargeted renal metabolomics and transcriptomics were integrated to identify potential pathways, followed by targeted biochemical and molecular validation. Indoxyl sulfate rescue experiments were performed to investigate the functional relationship between tryptophan metabolism and ferroptosis. Results: ART treatment significantly ameliorated CIS-induced renal dysfunction, as evidenced by reduced SCr and BUN levels and attenuated histopathological damage. These functional improvements were accompanied by marked suppression of pro-inflammatory cytokines and restoration of redox balance. Integrated renal metabolomic and transcriptomic analyses revealed that ART exerts its protective effects primarily through modulation of tryptophan metabolism and ferroptosis pathway. Subsequent validation confirmed that ART inhibited ferroptosis by reducing Fe ²⁺ accumulation, downregulating ACSL4 and FTL, and upregulating GPX4 and xCT. In HK-2 cells, indoxyl sulfate partially counteracted the cytoprotective and anti-ferroptotic effects of ART. Moreover, ART did not diminish CIS’s antineoplastic effect in human cancer cells. Conclusion: These findings demonstrate that ART alleviates CIS-induced nephrotoxicity by restoring tryptophan metabolic homeostasis and suppressing ferroptosis, positioning ART as a promising therapeutic candidate for preventing nephrotoxicity in patients undergoing CIS chemotherapy.