Circ Res. 2026 May 13. doi: 10.1161/CIRCRESAHA.125.327294. Online ahead of print.
ABSTRACT
BACKGROUND: Cardiac fibrosis is a major cause of cardiac dysfunction and is associated with virtually all forms of heart disease. Recently, single-cell genomic approaches have revealed in unprecedented resolution the orchestrated cellular responses driving cardiac fibrosis. Yet, the fibrosis-inducing phenotypes that emerge in the heart after nonischemic cardiac stress and the transcriptional circuits that govern fibrogenic cellular phenotypes are not well understood.
METHODS: Applying a single-cell paired-multiomic approach-by which both transcriptomic and epigenetic information is captured from individual cells-we reveal key transcription factors, in mouse and human hearts, associated with fibrosis development after nonischemic cardiac insults. Using high-throughput bulk transcriptomic and proteomic analyses, microscopy, and functional in vitro assays, we validate the distinct roles of new and established transcription factors in cardiac fibrosis.
RESULTS: Analysis of mouse hearts undergoing reverse remodeling after angiotensin II stimulation, where cardiac fibrosis dissipates, we find these factors are reversibly activated. Further, silencing transcription factors-including those we have identified that are previously unlinked to cardiac fibrosis, such as CREB3L2, BNC2, and NFAT5-modulates induction of extracellular matrix gene expression by human cardiac fibroblasts. Detailed analysis of CREB3L2 showed that it regulates cardiac fibrosis by modulating extracellular matrix synthesis through a dual mechanism-involving its N-terminal transactivation domain and a paracrine-acting C-terminal fragment-which is triggered after endoplasmic reticular stress.
CONCLUSIONS: This study identifies critical transcription factors regulating cardiac fibrosis and offers promising new targets to ameliorate the development of fibrosis in the context of stressors that cause cardiac dysfunction.
PMID:42125800 | DOI:10.1161/CIRCRESAHA.125.327294