Abstract
Fibroblasts are a special type of interstitial cell that has an essential role in maintaining the structural framework of tissues and organs. In response to injury, fibroblasts are activated and produce large amounts of extracellular matrix proteins. Fibroblast activation has a crucial role in tissue repair and wound healing. However, uncontrolled and persistent activation of fibroblasts ultimately leads to fibrotic diseases of organs such as the kidney, liver, lung and heart. Activated fibroblasts predominantly originate from the local activation and expansion of resident fibroblasts and pericytes. A diverse array of extracellular cues, including soluble factors, extracellular vesicles, matricellular proteins and mechanical stiffness, induce fibroblast activation after tissue injury. Fibroblast activation primarily takes place in the fibrogenic niche, a unique tissue microenvironment in which fibroblasts interact with injured parenchymal cells, inflammatory cells and endothelial cells. The fates of activated fibroblasts, including apoptosis, senescence, dedifferentiation and lineage reprogramming, determine the outcome of tissue repair and organ fibrosis. Potential therapeutic strategies for fibrotic diseases include disrupting the formation of the fibrogenic niche, inhibiting fibroblast activation, promoting fibroblast depletion, accelerating fibrosis resolution or promoting tissue repair and regeneration.
Key points
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Fibroblast activation is an evolutionarily conserved response to tissue injury. Dysregulated activation of fibroblasts results in excessive production of extracellular matrix (ECM) proteins, leading to tissue scarring in various organs.
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A diverse array of extracellular stimuli, including soluble factors, extracellular vesicles, matricellular proteins and mechanical cues, induce fibroblast activation after tissue injury. The TWA cycle, consisting of TGFβ, Wnt and angiotensin II, constitutes the core signalling network that drives fibrosis in various organs.
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Activation of fibroblasts primarily takes place in the fibrogenic niche, a specialized tissue microenvironment in which they interact with injured parenchymal cells, macrophages and endothelial cells via diverse mediators.
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Following tissue injury, the size of the fibroblast population is controlled not only by fibroblast activation but also by the speed of resolution of fibrosis; the fates of activated fibroblasts include apoptosis, senescence, dedifferentiation and reprogramming.
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Targeting fibroblasts could be an effective therapeutic strategy for organ fibrosis. Approaches that disrupt the formation of the fibrogenic niche, inhibit fibroblast activation or promote fibroblast depletion are promising strategies for ameliorating fibrotic lesions in various organs.
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Acknowledgements
We thank Dr. Li Li and other members of the Liu laboratory for many stimulating discussions. The author’s work was supported by the National Natural Science Foundation of China (NSFC) grants 82230020 and 82430026, the Key Technologies R&D Program of Guangdong Province (2023B1111030004), the Postdoctoral Fellowship Program of CPSF (GZB20240301) and funds from the Guangdong Provincial Clinical Research Center for Kidney Disease, Guangdong Key Laboratory of Organ Failure Research and Guangdong Provincial Institute of Nephrology.
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Y.L. conceived the article and provided the outlines of the manuscript. X.Z. and Y.Z. researched literature for the article, wrote the manuscript and created the figures. Y.L. wrote and revised the manuscript. All authors made substantial contributions to discussions of the content and edited the manuscript before submission.
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Zhang, X., Zhang, Y. & Liu, Y. Fibroblast activation and heterogeneity in fibrotic disease. Nat Rev Nephrol 21, 613–632 (2025). https://doi.org/10.1038/s41581-025-00969-8
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DOI: https://doi.org/10.1038/s41581-025-00969-8
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