Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis

Sangkyun Cho (), Siyeon Rhee, Christopher M. Madl, Arianne Caudal, Dilip Thomas, Hyeonyu Kim, Ana Kojic, Hye Sook Shin, Abhay Mahajan, James W. Jahng, Xi Wang, Phung N. Thai, David T. Paik, Mingqiang Wang, McKay Mullen, Natalie M. Baker, Jeremy Leitz, Souhrid Mukherjee, Virginia D. Winn, Y. Joseph Woo, Helen M. Blau and Joseph C. Wu ()
Additional contact information
Sangkyun Cho: Stanford University School of Medicine
Siyeon Rhee: Stanford University School of Medicine
Christopher M. Madl: Stanford University
Arianne Caudal: Stanford University School of Medicine
Dilip Thomas: Stanford University School of Medicine
Hyeonyu Kim: Stanford University School of Medicine
Ana Kojic: Stanford University School of Medicine
Hye Sook Shin: Stanford University School of Medicine
Abhay Mahajan: Stanford University School of Medicine
James W. Jahng: Stanford University School of Medicine
Xi Wang: Ohio State University
Phung N. Thai: Davis
David T. Paik: Stanford University School of Medicine
Mingqiang Wang: Stanford University School of Medicine
McKay Mullen: Stanford University School of Medicine
Natalie M. Baker: Stanford University School of Medicine
Jeremy Leitz: Greenstone Biosciences
Souhrid Mukherjee: Greenstone Biosciences
Virginia D. Winn: Stanford University School of Medicine
Y. Joseph Woo: Stanford University School of Medicine
Helen M. Blau: Stanford University School of Medicine
Joseph C. Wu: Stanford University School of Medicine

Nature, 2025, vol. 642, issue 8068, 766-775

Abstract: Abstract Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts1–6, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system7–10. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates—in concert with soluble regulators of the TGFβ pathway—a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGFβ suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF–SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.

Date: 2025
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DOI: 10.1038/s41586-025-08945-9

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