Integrated toxicogenomic and single-nucleus transcriptomic analyses prioritize SDHB and NDUFAB1 in mitochondrial respiration-associated remodeling during cisplatin-induced acute kidney injury

Abstract

Cisplatin-induced acute kidney injury (Cis-AKI) is a multifactorial nephrotoxic syndrome involving proximal tubular injury, oxidative and inflammatory stress, mitochondrial dysfunction, metabolic disturbance, and regulated cell death. However, the molecular targets linking cisplatin-associated toxicogenomic changes to AKI remain incompletely characterized. We integrated network toxicology, transcriptomic analysis, single-nucleus RNA sequencing, and in vitro experiments to investigate candidate molecular targets in Cis-AKI. Cisplatin-associated toxicogenomic genes were intersected with AKI-related genes, and the shared candidates were analyzed using functional enrichment, protein–protein interaction networks, CytoHubba, and MCODE. Prioritized genes were further examined in a cisplatin-induced mouse Acute kidney injury transcriptomic dataset, a human AKI kidney single-nucleus dataset, proximal tubular pseudotime analysis, and cisplatin-treated BUMPT proximal tubular cells. NicheNet analysis, knockout phenotype annotation, miRNA prediction, candidate compound screening, and molecular docking were also performed. A total of 214 shared genes were identified between the cisplatin-associated and AKI-related gene sets. These genes were mainly enriched in cellular respiration, electron transport, oxidoreductase activity, respiratory-chain complexes, and oxidative phosphorylation. Network analysis prioritized SDHB and NDUFAB1 within the respiration-associated gene network. In the cisplatin-induced mouse AKI dataset, Aco2, Aco1, Sdhb, and Aldh2 were significantly upregulated under stringent criteria, whereas additional respiration- and metabolism-related genes, including Ndufab1, met a secondary differential expression threshold. Human single-nucleus analysis revealed distinct cell-type-specific expression patterns of SDHB and NDUFAB1, with increased SDHB and decreased NDUFAB1 expression in proximal tubular cells. Pseudotime analysis showed a more pronounced late-stage increase in SDHB, whereas NDUFAB1 displayed weaker dynamics. In cisplatin-treated BUMPT cells, Havcr1 and Lcn2 were increased, Bcl2 was decreased, and Casp3 was increased. Among the selected candidate genes, Sdhb, Aco2, Aldh2, Ndufs2, and Uqcrc1 were upregulated, whereas Ndufab1 showed a modest decrease. NicheNet analysis further suggested that TGFB1-related signaling may contribute to proximal tubular transcriptional remodeling. This study prioritizes SDHB and NDUFAB1 within a respiration-associated gene network in Cis-AKI and demonstrates that they exhibit distinct expression patterns during proximal tubular injury. These findings highlight respiration-associated remodeling and proximal tubular state transition in cisplatin-induced kidney injury.