Single-cell and spatial transcriptomic insights into fibrotic mechanisms and therapeutic opportunities.

Fibrosis is a conserved response to chronic injury in which excessive extracellular matrix (ECM) deposition disrupts tissue architecture and organ function. Single-cell RNA sequencing and spatial transcriptomics now show that fibrosis is driven by multicellular niches rather than a uniform fibroblast population. We propose an ECM-associated mesenchymal cell (ECM-MC) continuum that links stromal progenitors, pericytes, fibroblasts and myofibroblasts across organs. This framework distinguishes conserved pathogenic states from tissue-specific adaptations and connects epithelial injury, immune-stromal crosstalk and matrix mechanics. We further evaluate therapeutic strategies that selectively target pathogenic ECM-MC states, interrupt fibrotic niches, modulate cellular plasticity and use multimodal data for patient endotyping and target prioritization.