Yang Zhang, Siyu Liu, Xiaoqi Li, Yuxin Zhou, Xinyan Wu, Haolan Yang, M Che, Xin Lei, Iram Laghari, Mingyue Wu, Ruilin Han, Haifeng Liu, Ziyao Zhou, Guangneng Peng, Kun Zhang, Zhijun Zhong
Background: (R-S) combination, a traditional Chinese herbal pair, has been used to treat acute kidney injury, but its mechanisms remain unclear. Objective: This study aimed to evaluate the nephroprotective effects of the R-S combination on cisplatin-induced AKI and to elucidate its underlying mechanisms through integrated multi-omics analyses. Methods: high-dose group (R-S-high), and curcumin group (Cur). AKI was induced by a single intraperitoneal injection of cisplatin (15 mg/kg). After the experiment, renal function was assessed by measuring serum creatinine (Cr) and blood urea nitrogen (BUN). Inflammatory cytokines and oxidative stress markers were detected using ELISA. Histopathological changes of the kidney tissue were evaluated by H&E staining. Gut microbiota composition, the cecal content metabolome and the renal transcriptome were further analyze. The MAPK signaling pathway in renal tissue was examined via RT-qPCR and Western blot. Results: R-S treatment significantly improved renal function, lowering Cr and BUN, and attenuated renal histopathological injury. It also reduced oxidative stress and inflammation, elevating SOD and GSH, while decreasing IL-1β and TNF-α. Gut microbiota analysis showed that R-S restored microbial diversity, suppressed Escherichia-Shigella, and promoted Lachnospiraceae_NK4A136_group. Metabolomics identified 1237 differential metabolites, with enrichment in linoleic acid metabolism. Transcriptomics revealed 3530 differentially expressed genes, primarily associated with the MAPK signaling pathway. Molecular validation confirmed that R-S downregulated the mRNA expression of IL-1β, IL-6, TNF-α, MAPK 14, MAPK 8, NFKB 1, FOS, and JUN, and suppressed the phosphorylation of p38 MAPK, JNK, and NF-κB p65. Conclusion: The R-S combination alleviates cisplatin-induced AKI by modulating the gut microbiota, regulating metabolic profiles, and suppressing the MAPK signaling axis. This study provides a holistic, multi-omics perspective on the mechanisms of R-S, supporting its potential as a therapeutic agent for AKI.