Multi-scale analysis reveals FGFR1 inhibition as effective strategy against cardiac fibrosis

Through a comprehensive approach combining transcriptomic profiling, histological analysis, and functional validation in organoid and animal models, a research team led by Associate Professor Yoshinori Yoshida and Assistant Professor Shunsuke Funakoshi has identified fibroblast growth factor receptor 1 (FGFR1) as a key therapeutic target for cardiac fibrosis in dilated cardiomyopathy (DCM).

DCM is a major cause of heart failure, characterized by ventricular dilation and impaired contractility. Cardiac fibrosis exacerbates disease progression by replacing functional myocardium with stiff, non-contractile tissue, yet targeted therapies remain scarce. To address this, the researchers analyzed myocardial biopsies from 58 DCM patients by integrating RNA sequencing data with AI-assisted histological analyses. Through this approach, they identified several genes, including MMP2, FGFR1, HRH2, and VIM, that correlated strongly with fibrosis severity.

To identify therapeutic targets from these genes, they used a human iPS cell-derived cardiac organoid fibrosis model. Through this approach, they found that administration of AZD4547, a selective FGFR1 inhibitor, significantly suppressed cardiac fibrosis. They further tested the effect of AZD4547 in a murine model of cardiac injury.

Remarkably, treatment suppressed fibrosis-related gene expression and reduced extracellular matrix deposition in both in vitro and in vivo fibrosis models. In mice, AZD4547 improved cardiac function and reversed fibroblast activation induced by angiotensin II and phenylephrine, suggesting its potential as a therapeutic agent for fibrotic heart disease.

Single-cell RNA sequencing further revealed that FGFR1 inhibition reduced pro-fibrotic FGF signaling between cardiomyocytes and fibroblasts, while enhancing NPR1 signaling—a pathway associated with cardioprotection. Specifically, AZD4547 increased the expression of Nppa and Nppb in cardiomyocytes, indicating a dual anti-fibrotic and cardioprotective effect.

Moreover, these molecular changes were accompanied by a shift in fibroblast populations toward a more quiescent phenotype and an increase in metabolically optimized cardiomyocytes, supporting the functional benefits observed. Notably, the study also demonstrated that FGFR1 activation is localized primarily to stromal cells rather than cardiomyocytes, reinforcing its role in driving fibrotic remodeling.

Unlike previous studies that relied solely on transcriptomic profiling, this work integrates automated histological analysis and functional validation, offering a more comprehensive view of fibrosis mechanisms and therapeutic responses. Given FGFR1’s role in fibrotic remodeling, its inhibition may hold therapeutic potential not only for DCM but also for other forms of heart failure characterized by excessive fibrosis.

The integrative methodology employed in this study—combining clinical biopsy data, transcriptomic analysis, histological quantification, and advanced in vitro and in vivo models—enabled the identification and validation of FGFR1 as a promising therapeutic target. This multi-scale approach not only strengthens the biological relevance of the findings but also provides a translational framework for future drug development.

Furthermore, the findings position FGFR1 inhibition as a compelling strategy for treating cardiac fibrosis and improving outcomes in DCM. Future clinical translation may involve stratifying patients based on FGFR1 activity or combining FGFR1 inhibitors with existing heart failure therapies to enhance efficacy.

The work is published in the journal JACC: Basic to Translational Science.