Abstract
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.