Comparative transcriptomics reveals shared stress and repair-associated pathway modules in proximal tubule cells exposed to platinum chemotherapeutics

Abstract

Platinum-based chemotherapeutics, including cisplatin, carboplatin, and oxaliplatin, are essential for treating solid malignancies but are limited by dose-dependent nephrotoxicity. The transcriptional programs shared across clinically used platinum agents in renal proximal tubule cells remain incompletely characterised, limiting the development of robust in vitro signatures for hazard identification and AOP development. Here, we performed comparative transcriptomic profiling and pathway enrichment analysis in conditionally immortalised proximal tubule epithelial cells exposed to low, subtoxic doses of cisplatin, carboplatin, or oxaliplatin. RNA-seq identified 1261 differentially expressed genes shared among all three compounds. Pathway enrichment analysis based on Reactome organised these shared genes into nine pathway clusters spanning genotoxic stress responses, proteostasis, cell cycle regulation, extracellular matrix (ECM) organisation, immune signalling, and tissue remodelling/repair-associated programmes. Several clusters, including proteasome-related processes, mitochondrial translation, ECM organisation, and Hedgehog/Wnt–planar cell polarity signalling, emerged as prominent shared features in this in vitro model and are prioritised here as candidate modules for follow-up testing. Collectively, these data provide a systems-level view of common transcriptional responses to three platinum agents in proximal tubule cells and nominate AOP-relevant candidate key-event–aligned transcriptional modules and shared transcriptomic signatures of proximal tubule stress/repair responses for subsequent dose–response, temporal, and functional validation.