Super-Enhancer-Targeted Regulation of Pulmonary Vascular Homeostasis and Its Therapeutic Potential
TANG Yujing, OU Langlin, WEN Shiqing, SHEN Ao, LI Ziru, MA Cui*
SE (super-enhancer) is a class of cis-regulatory elements composed of clusters of multiple enhancers that possess strong transcriptional activation capabilities. SEs drive the high expression of key genes by enriching high-density transcription factors, co-activators, and active histone modification marks. Studies have shown that SE plays critical regulatory roles in cell fate determination, maintenance of tissue homeostasis, and the onset and progression of diseases. Pulmonary vascular homeostasis relies on the fine-tuned transcriptional regulation and signaling synergy between endothelial cells and vascular smooth muscle cells. SE integrates multiple signals, including mechanical forces, metabolic signals, inflammatory responses, and hypoxia, to regulate the expression of key genes in pulmonary vascular-related cells, thereby participating in the maintenance of vascular function and pathological remodeling. In pulmonary hypertension, the SE-driven transcriptional regulatory network plays a key role in the pathology of various cell types, such as pulmonary arterial smooth muscle cells, pulmonary arterial en- dothelial cells, fibroblasts, and immune cells. SE contributes to pulmonary vascular remodeling and promotes the development and progression of various pulmonary diseases, including pulmonary hypertension, by regulating processes such as cell proliferation, phenotypic transformation, metabolic reprogramming, inflammatory signaling, and intercellular communication. Meanwhile, intervention strategies targeting SE-dependent transcriptional programs are continuously evolving, including small molecule inhibitors such as those targeting BET proteins and CDKs, CRISPR/Cas9-based gene editing and epigenomic editing technologies, regulatory strategies based on the three-dimensional structure of chromatin, and transcription factor-targeted degradation technologies. These approaches offer new insights into precision therapeutic strategies aimed at maintaining pulmonary vascular homeostasis by targeting SE. This article systematically reviews the fundamental characteristics of SE, their regulatory roles in pulmonary vascular homeostasis, and current research on potential therapeutic strategies targeting SE, providing a reference for mechanistic studies of related diseases and SE-targeted therapies.
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