Integrated multi-omics profiling identifies Cmpk1 as a monocyte-specific therapeutic target for renal ischemia-reperfusion injury

Background: Acute kidney injury (AKI) driven by ischemia-reperfusion injury (IRI) involves poorly defined immune-metabolic mechanisms. Although nucleotide metabolism dysregulation is implicated in tubular injury, its cell type-specific roles remain unexplored. We aimed to dissect cell -specific metabolic reprogramming in renal IRI and identify therapeutic targets.

Methods: We employed an integrative multi-omics strategy including bulk transcriptomics, metabolomics, single-cell RNA Sequencing, spatial transcriptomics, and functional validation through in vitro hypoxia-reoxygenation models and in vivo monocyte-specific gene knockdown using targeted viral vectors.

Results: Integrated omics revealed nucleotide metabolism dysregulation in IRI. Single-cell analysis demonstrated monocyte-specific upregulation of nucleotide metabolism compared to Other renal cell types. Machine learning prioritized Cmpk1, encoding a mitochondrial pyrimidine kinase, as the central hub gene. Cmpk1 elevation correlated with monocyte Pyroptosis, mitochondrial dysfunction, and pro-inflammatory cytokine secretion. Spatial transcriptomics confirmed Cmpk1 enrichment in tubulointerstitial monocytes. Cmpk1 knockdown in vitro attenuated hypoxia-reoxygenation injury, while its overexpression exacerbated mitochondrial damage and Pyroptosis. In vivo monocyte-specific Cmpk1 knockdown reduced renal functional impairment, tubular injury, oxidative stress, and inflammation.

Conclusion: Our study establishes Cmpk1-driven nucleotide metabolism in monocytes as a key regulator of AKI pathogenesis, orchestrating mitochondrial damage, Pyroptosis, and inflammation. Targeted inhibition of this pathway represents a promising therapeutic strategy.

Acute kidney injury; Cmpk1; Monocyte; Multi-omics; Nucleotide metabolism.