tRF-31-PS5P4PW3FJHP inhibits hypoxia-induced proliferation of pulmonary artery endothelial cells by regulating EDN1 splicing via binding to LSM4

Pulmonary hypertension (PH) is a severe vascular disease characterized by pulmonary vascular remodeling (PVR), in which the abnormal proliferation of pulmonary artery endothelial cells (PAECs) plays a crucial role. A large body of research has demonstrated that non-coding RNAs exert significant effects on the occurrence and progression of PH. As a novel type of non-coding small RNAs, tRNA-derived small RNAs (tsRNAs) are involved in the key regulation of various diseases processes. However, their specific roles and mechanisms in PH have not been fully explored. This study aims to clarify the involvement and molecular mechanisms of tsRNAs in PH-related PAEC proliferation. The research revealed that under hypoxic conditions, the expression of tRF-31-PS5P4PW3FJHP (tRF-31) is downregulated in lung tissues and PAECs, which is associated with downregulation of the Endonuclease Dicer. Overexpression of tRF-31 can inhibit hypoxia-induced proliferation of PAECs. Mechanistically, the reduction of tRF-31 under hypoxia leads to weakened binding between tRF-31 and LSM4, thereby decreasing the ubiquitination level of LSM4 and enhancing its protein stability. This increases the pool of free LSM4 that translocates into the nucleus and promotes the splicing of endothelin-1 (EDN1) precursor messenger RNA (pre-mRNA). Additionally, tRF-31 directly interacts with the 3' untranslated region (3' UTR) of EDN1 mRNA to reduce its degradation. These results suggest that tRF-31 may serve as a potential therapeutic target for PH.