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January 22nd, 2025
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Harbin Medical University
molecular biology
biorxiv

ca-circSCN8A promotes HPASMCs ferroptosis via LLPS initiated R-Loop

Li, M.Open in Google Scholar•Hao, Y.Open in Google Scholar•Song, X.Open in Google Scholar•Liu, H.Open in Google Scholar•Zhang, C.Open in Google Scholar•Zhang, J.Open in Google Scholar•Sun, H.Open in Google Scholar•Zheng, X.Open in Google Scholar•Zhang, L.Open in Google Scholar•Yu, H.Open in Google Scholaret al.

BACKGROUND: Ferroptosis has been implicated in pulmonary hypertension. Chromatin-associated RNAs are linked to ferroptosis. However, their role in pulmonary vascular ferroptosis in PH is unexplored. METHODS: Bioinformatics, Sanger sequencing, RNase R and others were employed to identify differentially higher expression of ca-circSCN8A. Functional gain and loss assays were employed to unveil the role of ca-circSCN8A in hypoxia-induced redox-dependent ferroptosis in HPASMCs and PH mice model. Interaction between ca-circSCN8A and FUS was detected via RNA immunoprecipitation and pull-down assays. FRAP, CHIRP-qPCR, MDA, GSH and GSSG were conducted to explore the potential molecular mechanism. RESULTS: ca-circSCN8A was firstly identified and confirmed to be upregulated in PH. Upregulation of ca-circSCN8A can promote hypoxia induced ferroptosis in HPASMCs. Under hypoxic conditions, ca-circSCN8A promoted the lactylation of FUS by recruiting EP300, leading to formation of LLPS of ca-circSCN8A/FUS/EP300. LLPS maintained the stability of the R-Loop formed by ca-circSCN8A and ferroptosis related-gene SLC7A11 promoter that inhibit the transcription of the SLC7A11 gene, further result in the disruption of the redox balance and causes ferroptosis in HPASMCs. CONCLUSIONS: ca-circSCN8A recruits EP300 to promote the lactylation of FUS, thereby promoting LLPS formation of ca-circSCN8A/EP300/FUS. Further, the LLPS motivates ca-circSCN8A to form R-loop with its non-host SLC7A11 and participating in the regulation of hypoxic induced HPASMCs redox-dependent ferroptosis. This is the first confirmation that circRNAs forming R-loops with non-host genes regulated by LLPS. Our findings indicated that ca-circSCN8A plays an important role in ferroptosis of hypoxic induced HPASMCs and may be a potential target for the treatment of PH.

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