Loss of KLF15 expression characterizes proximal tubule injury in cisplatin-induced acute kidney injury: A multi-omics study.

Nephrotoxicity is a common side effect of cisplatin (CSP), a widely-used anti-tumor chemotherapy drug. Acute kidney injury (AKI) induced by it is characterized by inflammation, apoptosis, and metabolic reprogramming in proximal tubule (PT) cells. However, the key pathways and upstream transcriptional regulators orchestrating these pathological changes remain poorly understood. This study aimed to identify crucial transcription factors (TFs) involved in CSP-induced AKI and to explore potential therapeutic agents targeting them. An integrative multi-omics analysis of public bulk RNA-seq, proteomic, and single-cell RNA-seq datasets was performed to identify dysregulated pathways and key TFs. The expression of Krüppel-like factor 15 (KLF15), the lead candidate TF, was validated in a CSP-induced AKI mouse model (20 mg/kg intraperitoneal injection for 72 h) using RT-qPCR and Western blot. Molecular docking utilizing AutodockVina was employed to virtually screen an FDA-approved drug library for potential compounds targeting KLF15.Transcriptomics and proteomics analyses consistently identified KLF15 as a top-ranked, downregulated TF in CSP induced AKI. Single-cell analysis revealed that PT cells were the most affected, and the loss of Klf15 expression in these cells was strongly associated with a proinflammatory, pro-apoptotic state and suppressed metabolic pathways, including the TCA cycle and fatty acid oxidation. In a murine model of CSP-induced AKI, Klf15 mRNA and KLF15 protein levels were markedly reduced. Furthermore, virtual screening identified 6 drugs, including Simeprevir, Lomitapide, and Avodart, as potential high-affinity compounds targeting human KLF15. In conclusion, our study indicates that the downregulation of KLF15 is a prominent molecular feature in CSP-induced AKI, associated with metabolic failure and injury in proximal tubules.