Ferroptosis inhibition as a renoprotective strategy in cisplatin-induced acute kidney injury: multilevel meta-analysis of mechanistic biomarkers

BackgroundCisplatin-induced acute kidney injury (CI-AKI) is a severe, dose-limiting nephrotoxicity affecting up to 30% of patients. Emerging evidence highlights ferroptosis—an iron-dependent form of regulated cell death—as a key mechanism in cisplatin-induced tubular damage. However, the overall effectiveness of various ferroptosis inhibitors remains unclear. This study aims to synthesise preclinical evidence to assess the renoprotective potential of natural and synthetic agents targeting the ferroptotic cascade.MethodsFollowing PRISMA 2020 guidelines, a systematic review and multilevel meta-analysis were conducted across PubMed and Web of Science. From 58 unique preclinical studies (265 effect sizes), we extracted data on renal function (BUN, SCr) and ferroptotic biomarkers (GPX4, GSH, MDA, 4-HNE, Fe2+). Standardised mean differences (Hedges’ g) were pooled using a three-level random-effects model, and moderators were assessed using multilevel meta-regression.ResultsBoth natural and synthetic interventions significantly alleviated renal dysfunction, markedly reducing BUN (Intercepts β = −3.84 and −4.06, respectively; p < 0.001) and serum creatinine. Outcome type emerged as a dominant moderator (QM > 500), with the most pronounced therapeutic shifts observed in the restoration of the antioxidant shield: GPX4 (β = 8.56 for natural, 8.71 for synthetic) and GSH (β = 6.99 for natural, 6.33 for synthetic) (p > 0.05). Significant residual heterogeneity was observed (QE, p < 0.001), and PET–PEESE analyses indicated small-study effects, suggesting that the magnitude of the pooled estimates may be inflated. Although the Trim and Fill adjustment did not alter the direction of findings, the overall results should be interpreted with caution.ConclusionInhibition of ferroptosis is a promising preclinical strategy to mitigate CI-AKI, with restoration of the System Xc−/GSH/GPX4 axis emerging as the primary mechanistic driver of renoprotection. These results provide a quantitative mechanistic consensus supporting further investigation and clinical development of ferroptosis-targeted adjuvants to widen the therapeutic window of cisplatin-based chemotherapy.