CD248 acts as a mechanosensory switch in fibroblast subsets to establish distinct pathological niches in renal fibrosis.

Although the heterogeneity and plasticity of fibroblasts are recognized hallmarks of tissue fibrosis, their specific contributions to renal fibrosis progression and the therapeutic validity of targeting key effector subsets remain key unanswered questions. Here, we revealed that diverse, functionally exclusive fibroblast subpopulations actively shape their local microenvironment. Pro-inflammatory fibroblasts (i-Fibs) construct immune-active areas, while pro-fibrotic fibroblasts (ECM-Fibs) generate fibrogenic zones. These two distinct microenvironments form a spatial mosaic, occupying mutually exclusive territories within the kidney tissue. We identified mechanotransduction as a signal governing the switch from i-Fibs to the pathogenic ECM-Fib phenotype. Through unbiased bioinformatics and genetic tools, we pinpointed CD248 as a specific cell-surface protein on this matrix-producing subset. Mechanistically, CD248, via its C-type lectin-like domain, senses the disordered matrix, promoting focal adhesion assembly and YAP nuclear translocation through an IQGAP1/ARF6-GTP-dependent axis, leading to a sustained feedback loop between aberrant matrix and myofibroblasts activation. A monoclonal antibody targeting CD248, IgG78, effectively interrupted this feedback loop, mitigating fibrogenesis both in vitro and in vivo in male mice. Collectively, this study established that fibroblast heterogeneity drives pathological niche specification in the fibrotic kidney and validated CD248 as a promising therapeutic target to counteract tissue fibrosis by disrupting aberrant mechanosignaling.