RNA-seq transcriptomic profiling reveals renoprotective mechanism of novel Psidium meroterpenoid derivatives (d)-G8 and (d)-G4 against cisplatin-induced acute kidney injury in human HK2 tubular epithelial cells

Cisplatin is a first-line chemotherapeutic agent for multiple solid tumors, but its severe nephrotoxicity severely limits clinical application and frequently induces acute kidney injury (AKI), which may further progress to chronic kidney disease. Psidium meroterpenoids from guava possess multiple pharmacological activities, and our previous study synthesized a series of novel Psidium meroterpenoid analogs with renoprotective potential. In this work, we systematically investigated the molecular mechanism of two lead chiral compounds (d)-G8 and (d)-G4 in alleviating cisplatin-induced renal injury via transcriptome sequencing. Human renal proximal tubular HK2 cells were used as the in vitro model, with 6 experimental groups (3 biological replicates per group, total 18 samples): untreated control group, 15 μM cisplatin injury model group, cisplatin + 2.5 μM (d)-G8 group, cisplatin + 10 μM (d)-G8 group, cisplatin + 2.5 μM (d)-G4 group, and cisplatin + 10 μM (d)-G4 group. Total RNA was extracted from all samples for paired-end RNA-seq on Illumina NovaSeq 6000 platform. Differential expressed genes (DEGs) were screened, followed by principal component analysis (PCA), Venn diagram analysis, heatmap clustering, GO and KEGG functional enrichment, as well as gene set enrichment analysis (GSEA). Transcriptomic results demonstrated that both (d)-G8 and (d)-G4 exerted significant renoprotective effects by upregulating copper efflux transporters ATP7A/ATP7B, activating AMPK-mediated autophagy pathway, improving mitochondrial homeostasis, and suppressing multiple inflammatory signaling cascades, with (d)-G8 showing more potent efficacy than (d)-G4. This RNA-seq dataset provides comprehensive transcriptional evidence for the anti-AKI activity of the two meroterpenoid derivatives, and identifies key gene targets and signaling pathways for the development of novel nephroprotective agents.