Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy.

Summary

Using isogenic hiPSC-derived models and engineered heart tissues, the authors show that loss of BAG3 in cardiac fibroblasts increases TGFBR2 abundance by impairing its ubiquitination and proteasomal degradation, sensitizing cells to TGF-β signaling and promoting fibrosis. Patient single-nucleus RNA-seq confirmed heightened fibrotic gene expression in fibroblasts harboring pathogenic BAG3 variants. This extends BAG3 biology beyond cardiomyocytes and nominates CF BAG3–TGFBR2 as an antifibrotic target.

Key Findings

• BAG3 loss in cardiac fibroblasts increased TGFBR2 levels by impeding its ubiquitination and proteasomal degradation.
• Engineered heart tissues with CF-specific BAG3 disruption recapitulated DCM-like contractile impairment and fibrosis.
• BAG3−/− CFs showed heightened sensitivity to TGF-β signaling under physiological stiffness (∼8 kPa).
• Single-nucleus RNA-seq from DCM patients with pathogenic BAG3 variants revealed increased fibrotic gene expression in CFs.

Clinical Implications

While preclinical, targeting the BAG3–TGFBR2 axis in cardiac fibroblasts could inform antifibrotic strategies for DCM beyond cardiomyocyte-focused approaches.

Limitations

• Primarily preclinical in vitro/engineered tissue models with limited in vivo validation.
• Patient single-nucleus datasets may have modest sample sizes and potential selection bias.

Future Directions

Test CF-targeted BAG3/TGFBR2 modulation in vivo, evaluate antifibrotic efficacy and safety, and explore biomarker strategies for patient selection.