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It often instigates in the focal sites by forming the fibrogenic niche after injury. In this study, using single\u2010cell RNA sequencing (scRNA\u2010seq) and a spatial transcriptomic (ST) approach, the cellular heterogeneity, spatial organization, and molecular interactions are delineated in the fibrotic kidney. Through analyses of the scRNA\u2010seq and ST data from normal and fibrotic kidneys in mice subjected to unilateral ischemia\u2010reperfusion injury, a tenascin C (TNC)\u2010enriched, proinflammatory, and profibrotic microenvironment is identified that facilitated macrophage activation and promoted renal inflammation and fibrosis. Both TNC\u2010enriched decellularized kidney tissue scaffold and exogenous TNC protein promoted bone marrow\u2010derived macrophages activation though Toll\u2010like receptor 4 (TLR4)\/NF\u2010\u03baB signaling. Either pharmacological inhibition of TLR4 signaling or genetic knockout of its gene alleviated renal inflammation and fibrosis by inhibiting macrophage activation in vivo. Finally, chimeric mice that received bone marrow transplantation from TLR4\u2010deficient donors are protected against kidney inflammation and fibrosis. These results suggest that TNC plays a crucial role in orchestrating the formation of a proinflammatory and profibrotic niche that promotes renal inflammation and fibrosis by activating macrophages via TLR4\/NF\u2010\u03baB signaling. The findings underscore the complex interplay among fibroblasts, extracellular microenvironment, and macrophages that drive kidney fibrosis.<\/jats:p>","DOI":"10.1002\/advs.202503691","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T13:22:18Z","timestamp":1759497738000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Single Cell and Spatial Transcriptomics Define a Proinflammatory and Profibrotic Niche After Kidney Injury"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7582-0511","authenticated-orcid":false,"given":"Li","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Multi\u2010organ Injury Prevention and Treatment National Clinical Research Center of Kidney Disease Division of Nephrology Nanfang Hospital Southern Medical University Guangzhou 510515 China"},{"name":"Guangdong Provincial Key Laboratory of 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