FGFR1 Inhibition: A Promising Approach to Combat Cardiac Fibrosis

Recent research has unveiled that inhibiting fibroblast growth factor receptor 1 (FGFR1) could serve as a potent therapeutic strategy against cardiac fibrosis, particularly in patients suffering from dilated cardiomyopathy (DCM), a leading cause of heart failure.

DCM is characterized by the enlargement of the heart's ventricles and reduced ability to contract, leading to severe health complications. Cardiac fibrosis plays a detrimental role in this condition by replacing normal heart muscle tissue with stiff, non-functioning fibrotic tissue. Unfortunately, effective therapies targeting this issue have been limited until now.

A research team from Kyoto University conducted a detailed investigation involving transcriptomic profiling, histological analysis, and functional validation through organoid and animal models. Their findings pinpointed FGFR1 as a crucial target for therapeutic intervention in cardiac fibrosis.

The study analyzed myocardial biopsies from 58 patients diagnosed with DCM, integrating RNA sequencing data with AI-assisted histological evaluations. This comprehensive analysis identified several genes, including MMP2, FGFR1, HRH2, and VIM, which exhibited strong correlations with the severity of fibrosis.

To further explore potential treatment options, the researchers employed a human induced pluripotent stem cell-derived cardiac organoid fibrosis model. They discovered that the selective FGFR1 inhibitor AZD4547 significantly reduced cardiac fibrosis. Subsequent tests in mouse models of cardiac injury confirmed that AZD4547 not only diminished the expression of fibrosis-related genes but also curtailed the deposition of extracellular matrix in both in vitro and in vivo settings. Notably, in mice, treatment with AZD4547 enhanced cardiac function and reversed fibroblast activation triggered by substances such as angiotensin II and phenylephrine, highlighting its therapeutic promise for fibrotic heart disease.

Further analysis using single-cell RNA sequencing indicated that inhibiting FGFR1 curtailed pro-fibrotic signaling pathways between cardiomyocytes and fibroblasts while simultaneously boosting NPR1 signaling, which is associated with protective effects on the heart. Specifically, treatment with AZD4547 elevated the expression of Nppa and Nppb genes in cardiomyocytes, suggesting a dual role in both combating fibrosis and offering cardioprotective benefits.

The observed molecular alterations were accompanied by a shift in fibroblast populations towards a more quiescent state and an increase in metabolically optimized cardiomyocytes, which supported the functional improvements noted in the study. Importantly, the research also established that FGFR1 activation predominantly occurs in stromal cells rather than in cardiomyocytes, emphasizing its significant role in the fibrotic remodeling process.

Unlike previous studies that focused solely on transcriptomic data, this research combined automated histological analysis with functional validation, providing a holistic understanding of the mechanisms underlying fibrosis and potential therapeutic responses. Given FGFR1's involvement in fibrotic remodeling, its inhibition presents a viable therapeutic avenue not only for DCM but also for other heart failure forms characterized by excessive fibrosis.

The integrative methodology utilized in this study, which combined clinical biopsy data, transcriptomic analysis, and advanced in vitro and in vivo models, successfully identified and validated FGFR1 as a promising target for therapy. This multi-scale approach enhances the biological significance of the findings and lays a groundwork for future drug development.

In conclusion, targeting FGFR1 emerges as a compelling strategy for addressing cardiac fibrosis and improving outcomes for patients with DCM. Future clinical applications may involve stratifying patients based on FGFR1 activity levels or combining FGFR1 inhibitors with existing heart failure treatments to improve their effectiveness.

This research is published in the journal JACC: Basic to Translational Science.