Biochemical and biophysical research communicationsAug 25, 2026

Fibroblast activation protein promotes heart support cell activity linked to reduced cell cleanup

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 26, 2026

Abstract

Fibroblast activation in dilated cardiomyopathy is associated with reduced expression of ER-phagy-related genes.

Fibroblast activation leads to increased myocardial fibrosis and impaired cardiac function.
Key genes involved in the selective autophagy pathway known as ER-phagy show decreased expression during fibroblast activation.
An activated population of fibroblasts with high levels of FAP exhibits a diminished transcriptional signature related to ER-phagy.
FAP induction is linked to a transcriptional program involving SMAD3, which represses certain ER-phagy genes.
Silencing FAP reduces fibroblast activation and ER stress while restoring expression of some ER-phagy-related transcripts.

Simplified

Dilated cardiomyopathy (DCM) is characterized by progressive myocardial fibrosis and extracellular matrix remodeling, which severely impair cardiac function. The endoplasmic reticulum (ER) is essential for collagen synthesis, but the role of ER-phagy, a selective autophagy pathway that maintains ER proteostasis, in pathological cardiac fibroblast activation remains unclear. We integrated single-cell RNA-seq, bulk RNA-seq, and ATAC-seq datasets from human cardiac tissue and cultured human and rat cardiac fibroblasts. Key findings were validated in TGF-β-treated primary neonatal rat cardiac fibroblasts using siRNA-mediated FAP silencing and autophagy-associated assays. Fibroblast activation was accompanied by reduced expression and promoter accessibility of selected ER-phagy-related genes. An FAP-high activated fibroblast population showed a lower ER-phagy-related transcriptional signature. Integrated regulon and promoter-motif analyses linked FAP induction to a SMAD3-centered, BET-sensitive transcriptional program associated with repression of a subset of ER-phagy genes. FAP silencing attenuated fibroblast activation and ER stress and was accompanied by restored expression of selected ER-phagy-related transcripts and changes in autophagy-associated markers. These findings support a role for FAP in cardiac fibroblast activation and link its induction to altered ER-phagy-related proteostasis and ER stress.

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Fibroblast activation protein promotes heart support cell activity linked to reduced cell cleanup

Abstract

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