Fibrosis: cross-organ biology and pathways to development of innovative drugs

Florian Rieder^#^{1

2

3}, Laura E Nagy^#^{4

5}, Toby M Maher^#^{6

7}, Jörg H W Distler^#^{8

9}, Rafael Kramann^#^{10

11}, Boris Hinz^#^{12

13}, Marco Prunotto^#¹⁴

Affiliations

¹ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. riederf@ccf.org.
² Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA. riederf@ccf.org.
³ Program for Global Translational Inflammatory Bowel Diseases (GRID), Chicago, IL, USA. riederf@ccf.org.
⁴ Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA.
⁵ Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA.
⁶ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ National Heart and Lung Institute, Imperial College, London, UK.
⁸ Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁹ Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
¹⁰ Department of Nephrology and Clinical Immunology, RWTH Aachen; Medical Faculty, Aachen, Germany.
¹¹ Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands.
¹² Keenan Research Institute for Biomedical Science of the St Michael's Hospital, Toronto, Ontario, Canada.
¹³ Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland. marco.prunotto@unige.ch.

^# Contributed equally.

PMID: 40102636
DOI: 10.1038/s41573-025-01158-9

Review

Fibrosis: cross-organ biology and pathways to development of innovative drugs

Florian Rieder et al. Nat Rev Drug Discov. 2025 Jul.

. 2025 Jul;24(7):543-569.

doi: 10.1038/s41573-025-01158-9. Epub 2025 Mar 18.

Authors

Florian Rieder^#^{1

2

3}, Laura E Nagy^#^{4

5}, Toby M Maher^#^{6

7}, Jörg H W Distler^#^{8

9}, Rafael Kramann^#^{10

11}, Boris Hinz^#^{12

13}, Marco Prunotto^#¹⁴

Affiliations

¹ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. riederf@ccf.org.
² Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA. riederf@ccf.org.
³ Program for Global Translational Inflammatory Bowel Diseases (GRID), Chicago, IL, USA. riederf@ccf.org.
⁴ Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA.
⁵ Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA.
⁶ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ National Heart and Lung Institute, Imperial College, London, UK.
⁸ Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁹ Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
¹⁰ Department of Nephrology and Clinical Immunology, RWTH Aachen; Medical Faculty, Aachen, Germany.
¹¹ Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands.
¹² Keenan Research Institute for Biomedical Science of the St Michael's Hospital, Toronto, Ontario, Canada.
¹³ Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland. marco.prunotto@unige.ch.

^# Contributed equally.

PMID: 40102636
DOI: 10.1038/s41573-025-01158-9

Erratum in

Publisher Correction: Fibrosis: cross-organ biology and pathways to development of innovative drugs.
Rieder F, Nagy LE, Maher TM, Distler JHW, Kramann R, Hinz B, Prunotto M. Rieder F, et al. Nat Rev Drug Discov. 2025 May;24(5):399. doi: 10.1038/s41573-025-01190-9. Nat Rev Drug Discov. 2025. PMID: 40164812 No abstract available.

Abstract

Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.

PubMed Disclaimer

Conflict of interest statement

Competing interests: F.R. is on the advisory board of or consultant to Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, AstraZeneca, Bausch & Lomb, Boehringer-Ingelheim, Celgene/BMS, Celltrion, CDISC, Celsius, Cowen, Eugit, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Janssen, Koutif, Mestag, Metacrine, Mirum, Mopac, Morphic, Myka Labs, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, Trix Bio, UCB, Ysios and 89Bio. J.H.W.D. has consultancy relationships with and/or is part of the speaker or advisory board of AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer-Ingelheim, Calliditas Therapeutics, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roche and UCB. J.H.W.D. has received research funding from Anamar, Argenx, ARXX, BMS, Bayer Pharma, Boehringer-Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Lassen, Sanofi-Aventis, RedX and UCB. J.H.W.D. is CEO of 4D Science and Scientific Lead of FibroCure. R.K. is founder and shareholder of Sequantrix GmbH and has grants from Travere Therapeutics, Galapagos, Chugai, AskBio and Novo Nordisk and is a consultant for Bayer, Roche, Chugai, Pfizer, Novo Nordisk, Hybridize Therapeutics and Gruenenthal. T.M.M., via his institution, has received industry-academic funding from AstraZeneca and GlaxoSmithKline R&D; and consultancy or speaker fees from AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, CSL Behring, Fibrogen, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Merck, Pliant, Pfizer, Qureight, Roche, Sanofi-Aventis, Structure Therapeutics, Trevi and Veracyte. M.P. is an employee of Medicxi Ventures. L.E.N. and B.H. declare no competing interests.

References

1. Hinz, B. et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am. J. Pathol. 180, 1340–1355 (2012). - PubMed - PMC - DOI
1. Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012). - PubMed - PMC - DOI
1. Henderson, N. C., Rieder, F. & Wynn, T. A. Fibrosis: from mechanisms to medicines. Nature 587, 555–566 (2020). - PubMed - PMC - DOI
1. Szaszi, K. & Amoozadeh, Y. New insights into functions, regulation, and pathological roles of tight junctions in kidney tubular epithelium. Int. Rev. Cell Mol. Biol. 308, 205–271 (2014). - PubMed - DOI
1. Selman, M. & Pardo, A. The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis. Cell Signal. 66, 109482 (2020). - PubMed - DOI

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Fibrosis: cross-organ biology and pathways to development of innovative drugs

Affiliations

Fibrosis: cross-organ biology and pathways to development of innovative drugs

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources