Super-Enhancer-driven LncRNA UNC5B-AS1 Inhibits Inflammatory Phenotypic Transition in Pulmonary Artery Smooth Muscle Cells via Lactylation

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 (PH). Super-enhancers (SEs) are characterized by histone modifications and the binding of coactivators, which drive the expression of prominent genes which define cellular identity. The specific role of SEs, especially SE-driven long non-coding RNAs (lncRNAs), in hypoxia-induced phenotypic plasticity of PASMCs remains unclear. Methods: In this study, the lncRNA UNC5B-AS1 regulated by SEs was screened in hypoxic PASMCs using RNA sequencing and H3K27ac chromatin immunoprecipitation (ChIP) sequencing. Overexpression or knockdown of UNC5B-AS1 in vitro was performed to elucidate its role in PH pathogenesis. A serotype 5 adenovirus-associated virus carrying a conserved functional fragment of UNC5B-AS1 was used to treat PH in vivo. Results: We identified UNC5B-AS1 as an SE-driven lncRNA transcriptionally activated by the transcription factor FOXP3, 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 Leucine-Rich PPR Motif-Containing Protein (LRPPRC) and oxidative respiratory chain complex IV in the mitochondria. Consequently, the deficiency of UNC5B-AS1 in PASMCs promotes the lactylation of promoter regions within inflammatory genes, including those of IL-1β, IL-6, and TNF-α, under hypoxic conditions, ultimately leading to 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 PH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288999 | GEO | 2025/05/01

REPOSITORIES: GEO