Abstract
Systemic sclerosis (SSc) is a prototypical systemic immune-mediated fibrosing disease that affects the skin, the lungs, the heart, the kidneys and the intestinal tract. Similar to many other fibrotic diseases, SSc is associated with high morbidity and mortality and therapeutic options are limited. Fibrosis arises from a complex interplay of vascular damage, inflammation and prolonged, misdirected repair responses. The progressive accumulation of extracellular matrix perturbs the physiological tissue architecture and commonly leads to failure of the affected organs. Understanding the mechanisms of fibrotic tissue remodelling can lead to the identification of preclinical targets. Novel fibrosis-promoting cell subpopulations, the interplay of fibroblasts with B cells and macrophages, the nerve–fibroblast axis, matrikines and matricryptins, senescence, profibrotic transcription factors, developmental pathways and epigenetic tissue memory are all important drivers of fibrotic tissue remodelling that might offer potential for novel therapies to improve outcomes for patients with SSc and possibly other fibrotic conditions.
Key points
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The pathogenesis of systemic sclerosis (SSc) is characterized by an interplay of vascular damage, autoimmunity-induced inflammation and fibrotic tissue responses.
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These processes are highly interlinked and are active throughout all stages of the disease, although their relative contribution to disease progression can vary at different disease stages and in different patient populations.
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Advances in omics technologies have enabled identification and phenotyping of different cellular subpopulations with diverse functions in the pathogenesis of SSc.
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Interactions between leukocyte subpopulations, such as B cells and macrophages, and fibroblasts have an important role in disease progression.
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Molecular drivers of SSc include, but are not limited to, the nerve–fibroblast axis, matrikines, senescence, JAK–STAT signalling, nuclear receptors and other profibrotic transcription factors, developmental pathways and epigenetic tissue memory.
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Acknowledgements
J.H.W.D. acknowledges the following grants: DI 1537/20-1, DI 1537/22-1, DI 1537/23-1, DI1537/27-1, DI 1537/28-1 from the German Research Foundation and projects from the research council (Forschungskommission) of the Medical Faculty of the Heinrich-Heine-University, as well as an unrestricted research grant from the Hiller-Foundation. D.L. acknowledges unrestricted research grants from GCS G4 and AVIESAN; grants from the European Union through the European Regional Development Fund (ERDF) within the framework of the Contrat de Plan Etat-Région (CPER) 2021–2027 for the Hauts-de-France region, France; as well as an unrestricted research grant from the University of Lille (Cross Disciplinary Program). A.-E.M. acknowledges the following grants: MA 9219/2-1 and 493659010 of the German Research Foundation, grants 2021_EKEA.03 and 2022_EKMS.02 of the Else-Kröner-Fresenius-Foundation, The Edith Busch and World Scleroderma Foundation Research Grant Programme 2022–2023 and the Research Committee of the Medical Faculty of the Heinrich-Heine University Düsseldorf (Forschungskommission; ID 2023-33). J.E.G. acknowledges an unrestricted research grant from the Taubman Medical Research Institute.
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J.H.W.D. has consulted for Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Callidatas, Calluna, Galapagos, GSK, Janssen, Kyverna, Novartis, Pfizer, Quell Therapeutics and UCB; has received research funding from Anamar, ARXX, BMS, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Exo Therapeutics, Galapagos, GSK, Incyte, Inventiva, Kiniksa, Kyverna, Lassen Therapeutics, Mestag, Sanofi-Aventis, SpicaTx, RedX, UCB and ZenasBio; is the CEO of 4D Science and scientific lead of FibroCure. D.L. has consulted for AstraZeneca, Boehringer Ingelheim, CSL Behring, Biocryst, Takeda; has received research funding from Boehringer Ingelheim, Roche, CSL Behring, Biocryst and Servier. J.E.G. has consulted for Eli Lilly, Janssen, Johnson & Johnson, Incyte, BMS, Sanofi, Prometheus, Almirall, Kyowa-Kirin, Novartis, AnaptysBio, Boehringer Ingelheim, GSK, AbbVie and Galderma; has research funding from Almirall, AbbVie, Boehringer Ingelheim, GSK, Galderma, Novartis, Johnson & Johnson and Eli Lilly.
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Distler, J.H.W., Launay, D., Feghali-Bostwick, C. et al. Mechanisms of fibrotic tissue remodelling: insights from systemic sclerosis. Nat Rev Rheumatol 22, 221–238 (2026). https://doi.org/10.1038/s41584-025-01349-z
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DOI: https://doi.org/10.1038/s41584-025-01349-z
