Key result
Fibroblast YAP activation drives atrial fibroinflammation via glycolysis and macrophage crosstalk.
Why the study?
The mechanisms underlying chamber-specific transcriptomic and metabolic differences in the heart, and how YAP regulates the metabolic microenvironment during homeostasis and fibroinflammation, remain poorly understood.
Chamber-specific YAP activation in right atrial cardiac fibroblasts drives glycolysis, disrupts lineage fidelity, and promotes reciprocal macrophage signaling to induce fibroinflammation.
YAP inhibition may curb right atrial fibroinflammation; leaves open translation beyond mouse models.
BACKGROUND: Separation of the pulmonic and systemic circulation is essential for terrestrial life, and mammals have evolved distinct cardiac chambers with specialized structures and functions. Transcriptomics profiling revealed cellular heterogeneity between heart chambers. However, the mechanisms underlying chamber-specific transcriptomic and metabolic differences-and their functional significance-remain poorly understood. The Hippo/YAP (yes-associated protein) pathway is a conserved signaling network that regulates diverse cellular processes. The Hippo kinases inhibit YAP in cardiac fibroblasts (CF) to restrict fibrosis and inflammation. Nonetheless, how YAP regulates the metabolic microenvironment during homeostasis and fibroinflammation remains unclear. METHODS: , in mouse CFs and performed metabolic studies, snRNA-seq, single-nucleus assay for transposase-accessible chromatin with sequencing, and spatial transcriptomics. RESULTS: Metabolic and sequencing approaches revealed that Hippo-deficient CFs activated glycolysis to promote fibroinflammation. Inhibition of glycolysis or lactate production suppressed Hippo-deficient CF-induced fibrosis. Elevated YAP activity disrupted fibroblast lineage fidelity by inducing an osteochondroprogenitor cell state. Blocking macrophage expansion pharmacologically reduced Hippo-deficient CF proliferation and fibrosis. Sequencing and functional studies showed that macrophages secreted IGF1 (insulin-like growth factor 1) to activate IGF1 signaling in Hippo-deficient CFs to increase cell proliferation and fibrosis. CONCLUSIONS: We discovered that right atrial CFs are more glycolytic and have higher YAP activity than CFs in other heart chambers. YAP activation in CFs induces glycolysis to drive fibrosis. YAP disrupts fibroblast lineage fidelity, driving them to a SOX9 (SRY-box transcription factor 9)-expressing osteochondroprogenitor cell state. Mechanistically, YAP activates the secretion of CSF1 (colony-stimulating factor 1) to promote macrophage expansion. Blocking macrophage expansion reduces Hippo-deficient CF proliferation, osteochondroprogenitor differentiation, and fibrosis, revealing that macrophages signal reciprocally to regulate CF cell states. Genomic and functional studies revealed that the upregulated IGF1 receptor in Hippo-deficient CFs enables them to receive macrophage-secreted IGF1, thereby further enhancing CF proliferation and fibrosis.
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Tsai et al. (2025) studied Cardiac fibrosis and inflammation. Lats1/2 deletion (Hippo pathway deficiency) vs. Control mice was evaluated on Cardiac fibrosis, fibroblast proliferation, and osteochondroprogenitor differentiation. YAP activation in right atrial cardiac fibroblasts induces glycolysis and an osteochondroprogenitor state, driving fibroinflammation through a reciprocal signaling loop with macrophages.
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