Work

Temporal multi-omics reveals regulatory transitions and renoprotective candidates in cisplatin-induced kidney injury

Year: 2026

Type: article

Abstract: Cisplatin is a classic first-line platinum drug extensively used in chemotherapy for solid tumors, yet its clinical applications are limited by dose-dependent nephrotoxicity. The dynamic molecular mechanisms underlying cisplatin-induced kidney injury and regeneration remain incompletely understood. Here, we established two complementary mouse models, a single high-dose cisplatin (SHDC) model and a repeated low-dose cisplatin (RLDC) model, to recapitulate acute and progressive/persistent patterns of renal injury, respectively. Integrated transcriptomic and proteomic analyses reveal temporal transcript-protein discordance and persistent molecular remodeling. Temporal analysis of protein regulatory dynamics suggests that progression from acute to persistent kidney injury involves a shift from metabolic and xenobiotic-handling responses toward sustained stress and inflammatory programs. Multi-omics factor analysis and random forest modeling prioritize six candidate regulatory genes (NFKB2, JUNB, TNFAIP3, PROS1, NFKBIA, and S100A11) with discriminative value in human AKI cohorts. Upstream transcriptional factor analysis identifies TP53 and STAT1 as critical regulatory nodes. Transcriptome signature-based drug prioritization identifies candidate compounds capable of reversing the molecular signature associated with cisplatin injury, and we validated the renoprotective effects of CGP60474 and A-443654 in both in vitro and in vivo settings. Lastly, we constructed a publicly accessible, interactive Mouse Cisplatin Nephrotoxicity Omics Database (MCNOD) to facilitate data mining and exploration. Collectively, these findings provide critical insights into the dynamic regulatory mechanisms underlying cisplatin nephrotoxicity and contribute to the development of targeted renoprotective strategies.

Source: Molecular & Cellular Proteomics

DOI: 10.1016/j.mcpro.2026.101691