LINC03047 promotes mitophagy by recruiting hnRNPF to enhance CTGF mRNA stability in hypoxic pulmonary hypertension

Pulmonary hypertension (PH) is a progressive and debilitating vascular disorder characterized by pulmonary vascular remodeling, primarily driven by the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). In this pathogenic process, Mitophagy, a selective form of Autophagy, has been identified as playing a pivotal role. Long non-coding RNAs (lncRNAs) are increasingly recognized as significant regulatory elements in various diseases; however, their specific functions in the context of PASMCs Mitophagy and proliferation remain largely unexplored. This study aims to investigate the role of a hypoxia-associated lncRNA, long intergenic non-protein coding RNA 3047 (LINC03047), in modulating Mitophagy and cellular proliferation in hypoxia-induced PASMCs. Our findings reveal that LINC03047 is significantly upregulated in PASMCs under hypoxic conditions and promotes cell proliferation by activating Mitophagy. Mechanistically, we demonstrate that LINC03047, which is transcriptionally regulated by the signal transducer and activator of transcription 3 (STAT3), physically binds to heterogeneous nuclear ribonucleoprotein F (hnRNPF). This interaction inhibits the nuclear translocation of hnRNPF and enhances the stability of connective tissue growth factor (CTGF) mRNA, thereby amplifying its downstream effects. Furthermore, in vivo experiments confirmed that targeted inhibition of hnRNPF effectively mitigates the development of hypoxia-induced PH in model systems. Collectively, these findings elucidate a novel regulatory axis and demonstrate that targeting the STAT3/LINC03047/hnRNPF/CTGF signaling pathway offers a promising therapeutic strategy for the treatment of PH.

Long non-coding RNAs; Mitophagy; Pulmonary hypertension; hnRNPF.