Life sciences · 2025
Integrated multi-omics profiling identifies Cmpk1 as a monocyte-specific therapeutic target for renal ischemia-reperfusion injury.
СтатьяНазвание и аннотация: Перевод в очереди
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Zhang Haoxun, Zhang Guoling, Wang Bowen, Xiong Feng, Ji Xuran, Wang Chunyang
Аннотация
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.
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.