YAP-Induced Glycolysis Drives Fibroinflammation and Disrupts Fibroblast Fidelity

作者：Chang-Ru Tsai, Lin Liu, Yi Zhao, J H Kim, Paulo Czarnewski, Gang Li, Fansen Meng, Mingjie Zheng, Jeffrey D. Steimle, Xiaolei Zhao, Francisco Grisanti, Zheng Sun, Jun Wang, Md. Abul Hassan Samee, Xiao Li, James F. Martin · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.125.326480 · 被引用次数：7 · 研究领域：Hippo pathway signaling and YAP/TAZ、Cardiac Fibrosis and Remodeling、IL-33, ST2, and ILC Pathways

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 si...