Epigenetically activated MIR100HG regulates UPF1-mediated oxidative stress to promote pulmonary vascular immune...

Oxidative stress is positively associated with vascular remodeling and immune microenvironment imbalance in pulmonary hypertension (PH). However, the precise molecular mechanisms involving epigenetic modifications in this process remain unclear. The study aims to systematically identify chromatin remodeling-associated long non-coding RNAs (lncRNAs) and elucidate their regulatory networks in oxidative stress-dependent PH pathogenesis. ChIP-sequencing identified MIR100HG as a hypoxia-induced differentially expressed lncRNA in pulmonary artery smooth muscle cells (PASMCs), characterized by histone modifications and coactivator binding. Both in vitro and in vivo studies demonstrated that elevated MIR100HG expression promotes oxidative stress-mediated dynamic interactions within the immune microenvironment, creating a cascade amplification effect that ultimately induces PASMC proliferation. Mechanistically, the transcription factor RELA (also known as nuclear factor kappa B p65) upregulates MIR100HG expression by binding to chromatin remodeling regions. Through mass spectrometry analysis, RNA-pulldown assays, and RNA immunoprecipitation (RIP) experiments, we further identified regulator of nonsense transcripts 1 (UPF1) as a direct binding target of MIR100HG. Specifically, MIR100HG interacts with UPF1 and modulates its binding to the mRNA of nuclear factor erythroid 2-related factor 2 (NRF2), a key antioxidant response regulator, thereby attenuating its transcription. Furthermore, single-cell sequencing data analysis reveals that under hypoxic conditions, MIR100HG regulates the IBSP-ITGAV interaction, thereby promoting macrophage activation and reshaping the immune microenvironment in the pulmonary vasculature. Our study demonstrates that the MIR100HG/UPF1/NRF2 signaling axis regulates oxidative stress and PASMC proliferation, ultimately leading to macrophage recruitment and vascular immune microenvironment imbalance. This pathway represents a promising target for early diagnosis and therapeutic intervention in PH.