Sex-dependent transcriptional responses and druggable targets in gentamicin-induced nephrotoxicity

Gentamicin is a potent aminoglycoside antibiotic, but its clinical use is limited by severe nephrotoxicity. Experimental and transcriptomic studies have indicated that the extent of renal injury and recovery following gentamicin exposure may differ between sexes, yet the underlying molecular mechanisms remain poorly understood. In this study, we investigated sex-specific transcriptional signatures, hub genes, transcription factors, and druggable molecular pathways involved in gentamicin-induced kidney injury and recovery. RNA-seq data from rat kidney tissues (male, female, and combined groups) were obtained from the NCBI-GEO database and analyzed at two time points corresponding to injury (day 15) and recovery (day 29). Differentially expressed genes were identified and subjected to functional enrichment (GO/KEGG), hub gene, and transcription factor detection analyses, followed by drug-gene interaction screening using DGIdb. Males exhibited a broader but more homogeneous transcriptional response, whereas females showed a narrower yet more pronounced activation pattern. A conserved mitotic core (BIRC5, BUB1B, CCNA2, CDC20) was shared across sexes and phases. Sex-dependent divergence emerged primarily during the recovery phase: PBK, CCNB1, and NUF2 were identified as female-specific proliferative hubs, whereas CDCA8 was uniquely enriched in males. Transcription factors CENPA, FOXM1, and MYBL2 formed a shared regulatory backbone, while DNMT1 appeared predominantly in male injury samples, suggesting a male-biased epigenetic component. DGIdb integration showed that among sex-specific hub genes, only CCNB1 had druggable interactions, whereas PBK, NUF2, and CDCA8 lacked pharmacological matches. In contrast, several core cell-cycle regulators (BIRC5, BUB1B, BUB1, CCNA2, CDK1) were highly druggable. These findings demonstrate that gentamicin nephrotoxicity is governed by a shared cell-cycle core but modulated by sex-specific repair programs, providing a molecular basis for the development of sex-tailored therapeutic strategies.