Super-Enhancer–Driven LncRNA UNC5B-AS1 Inhibits Inflammatory Phenotypic Transition in Pulmonary Artery Smooth Muscle Cells via Lactylation
Xiangrui Zhu, Xiangming Pang, Xiaoying Wang, Xiaoyu Guan, Yujing Tang, Zhaosi Wang, Lixin Zhang, Xiaodong Zheng, Fei Li, Jian Mei, Langlin Ou, Yuxiang Liu, Zitong Meng, Yingli Chen, Cui Ma
Abstract
BACKGROUND: The phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) is a central pathological alteration in pulmonary artery remodeling, contributing to pulmonary hypertension. Super-enhancers (SEs), characterized by histone modifications and the binding of coactivators, drive the expression of prominent genes that define cellular identity. However, the specific role of SEs, particularly SE-driven lncRNAs (long noncoding RNAs), in hypoxia-induced phenotypic plasticity of PASMCs remains unclear. METHODS: In this study, the lncRNA UNC5B antisense RNA 1 (UNC5B-AS1) regulated by SEs was screened in hypoxic PASMCs using RNA sequencing and H3K27ac (histone 3 lysine 27 acetylation) ChIP (chromatin immunoprecipitation) sequencing. Overexpression or knockdown of UNC5B-AS1 in vitro was performed to elucidate its role in pulmonary hypertension pathogenesis. A serotype 5 adenovirus-associated virus carrying a conserved functional fragment of UNC5B-AS1 was used to treat pulmonary hypertension in vivo. RESULTS: We identified UNC5B-AS1 as an SE-driven lncRNA transcriptionally activated by the transcription factor FOXP3 (forkhead box protein P3), which regulates phenotypic transition in PASMCs. Notably, we demonstrated that UNC5B-AS1 interacts with key glycolytic enzymes in the cytoplasm and likely serves as a molecular scaffold for LRPPRC (leucine-rich PPR motif-containing protein) and oxidative respiratory chain complex IV in mitochondria. Consequently, the deficiency of UNC5B-AS1 in PASMCs promotes the lactylation of promoter regions within inflammatory genes, including those of IL (interleukin)-1β, IL-6, and TNF-α (tumor necrosis factor-α), under hypoxic conditions, ultimately leading to inflammatory phenotypic transition of PASMCs. CONCLUSIONS: Our findings identify SE-driven UNC5B-AS1 as a novel regulatory factor in the hypoxia-induced phenotypic transition of PASMCs and suggest that overexpression of UNC5B-AS1 may represent a promising therapeutic strategy for pulmonary hypertension.