Spatial metabolomics and transcriptomics reveal the metabolic-immune niche associated with renal fibrosis in...

Hyperuricemic nephropathy (HN) represents a major contributor to chronic kidney disease and is marked by progressive renal fibrosis accompanied by profound metabolic disturbances. Despite its clinical importance, the spatial coordination between metabolic remodeling and intercellular communication within the HN microenvironment remains poorly defined.

To address this gap, we generated a comprehensive, high-resolution multi-omic atlas of kidneys from a hyperuricemic mouse model by integrating spatial metabolomics, single-cell RNA sequencing, and spatial transcriptomics. Key findings were further validated using multiplex immunohistochemical analyses.

A metabolic signature consistent with hypoxic adaptation was observed within hyperuricemic kidneys, characterized by a predicted metabolic shift toward anaerobic glycolysis based on computational flux inference and impaired mitochondrial function, as evidenced by marked lactate accumulation and depletion of citrate. Within this metabolically compromised environment, we observed the selective expansion and spatial co-localization of Cxcl14⁺ fibroblasts and Vim⁺ macrophages. Computational analyses suggest that these pathogenic cell populations may engage in a self-reinforcing feedback circuit: macrophage-derived tumor necrosis factor (TNF) activates fibroblasts through NF-κB signaling, while fibroblast-secreted transforming growth factor-β (TGF-β) maintains macrophages in a profibrotic state. These data support a candidate reciprocal signaling interaction that may contribute to chronic inflammation and fibrosis under conditions of metabolic stress.

This study establishes a hypothesis-generating multi-omic framework delineating the spatial proximity of metabolic and immune-stromal alterations in HN. By mapping metabolic alterations consistent with hypoxic adaptation to defined cellular interactions, our findings suggest that targeting hypoxia-dependent fibroblast-macrophage crosstalk may represent a promising therapeutic strategy for limiting renal fibrosis.