Targeting FGFR1 as a Promising Therapeutic Strategy Against Cardiac Fibrosis

Recent research leveraging multi-scale analysis methods has highlighted the potential of FGFR1 inhibition in treating cardiac fibrosis, a key contributor to heart failure in dilated cardiomyopathy (DCM). Conducted by a team led by Associate Professor Yoshinori Yoshida and Assistant Professor Shunsuke Funakoshi at Kyoto University, the study combined transcriptomic profiling, histological examination, and functional validation using organoid and animal models.

Cardiac fibrosis involves the excessive accumulation of extracellular matrix components, which stiffens the heart tissue and impairs its function. This process significantly worsens disease progression in DCM, a major cause of heart failure characterized by ventricular dilation and decreased contractility. Despite its impact, targeted therapies for fibrosis remain limited.

The researchers analyzed myocardial biopsies from 58 DCM patients and integrated RNA sequencing with AI-assisted histology, identifying several genes correlated with the severity of fibrosis, including MMP2, FGFR1, HRH2, and VIM. Focusing on FGFR1, they used a human iPS cell-derived cardiac organoid model to test its role and discovered that the drug AZD4547, a selective FGFR1 inhibitor, notably suppressed fibrotic activity.

Further validation in mouse models demonstrated that AZD4547 reduced fibrosis-related gene expression and extracellular matrix build-up. The treatment improved cardiac function and reversed activation of fibroblasts induced by hypertrophic stimuli like angiotensin II and phenylephrine. Single-cell RNA sequencing revealed that FGFR1 inhibition dampened pro-fibrotic FGF signaling between cardiomyocytes and stromal cells while boosting NPR1 signaling, which is linked to cardioprotection. Increased levels of Nppa and Nppb in cardiomyocytes after treatment suggest dual benefits: anti-fibrotic effects and enhanced heart resilience.

Additionally, these molecular changes facilitated a shift of fibroblast populations toward a quiescent phenotype and increased metabolically optimized cardiomyocytes, contributing to improved cardiac performance. Notably, FGFR1 activation was primarily localized in stromal cells, emphasizing its role in fibrotic tissue remodeling.

Unlike earlier studies that relied solely on transcriptomics, this research integrated automated histological analysis and functional testing, providing a comprehensive view of fibrosis mechanisms. The findings underscore FGFR1's crucial role in fibrotic remodeling and indicate that its inhibition could serve as an effective therapy for DCM and potentially other heart failure forms involving fibrosis.

This innovative approach, combining clinical biopsies, molecular analysis, and advanced models, offers a promising translational pathway for drug development. The results support further clinical exploration of FGFR1 inhibitors, possibly in combination with existing treatments, to improve outcomes for patients with fibrotic heart disease.

The full study is published in "JACC: Basic to Translational Science" and underscores the therapeutic potential of FGFR1 targeting in cardiac fibrosis management.