Fibroblast phenotypic plasticity: molecular mechanisms, context-dependent regulation, and clinical translation challenges— A comprehensive review

Background Over the past century, fibroblasts were long regarded as homogeneous, passive connective-tissue cells, with their remarkable functional diversity and phenotypic plasticity largely overlooked. The rapid advancement of single-cell/spatial omics and genetic lineage tracing technologies over the past decade has revolutionized this conventional view, confirming that dynamic fibroblast phenotypic switching is a central process governing tissue homeostasis, adaptive injury repair, and the pathogenesis of diverse human diseases. Nevertheless, critical gaps remain in our understanding: there is a lack of systematic integration of multi-layered regulatory mechanisms underlying fibroblast phenotypic plasticity, and the context-dependent modulation rules across different organs and disease states remain poorly defined, which significantly hinders the translation of basic fibroblast biology into clinical applications. Methods This narrative review addresses these gaps by first delineating the core biological characteristics of fibroblasts, clarifying their lineage boundaries with related mesenchymal cell types, and tracing the four-stage historical evolution of fibroblast plasticity research. We then systematically dissect the integrated regulatory network driving fibroblast phenotypic switching, including soluble biochemical signals, mechanical microenvironmental cues, cell-extracellular matrix (ECM) crosstalk, epigenetic modifications, and emerging metabolic regulators. Furthermore, we elaborate on how tissue-specific microenvironments, ECM properties, and intercellular communication shape context-dependent fibroblast phenotypic outcomes, with a particular focus on skin, lung, kidney, and heart. Finally, we analyze the major challenges facing clinical translation of fibroblast-targeted therapies and outline key future research directions. Conclusions This review constructs a unified theoretical framework for fibroblast phenotypic plasticity regulation, provides a systematic reference for basic fibroblast biology research, and lays a mechanistic foundation for the development of precise, subtype-specific fibroblast-targeted interventions.