Cerebral ischemia leads to progressive neurological dysfunction due to restricted blood perfusion in the brain. While circular RNAs are known to regulate pathological processes, their ability to encode functional proteins during ischemic injury remains unclear. Here, we show that the circular RNA circAbcc1 suppresses ferroptosis in mouse and cellular models of chronic cerebral ischemia‘.
We found that circAbcc1 translates into a functional protein, ABCC1-677aa. This protein actively interacts with and phosphorylates the transcription factor DLX1, triggering its export from the nucleus to the cytoplasm. This translocation prevents DLX1 from transcriptionally repressing the crucial anti-ferroptotic genes, Gpx4 and Fsp1.
The subsequent upregulation of Gpx4 and Fsp1 limits lipid peroxidation and iron accumulation, successfully protecting brain neurons from ferroptosis. These findings elucidate a regulatory mechanism driven by a circular RNA-encoded protein and identify the circAbcc1-DLX1 axis as a potential therapeutic target for cerebral ischemic injury. This work is supported by the Education Department of Liaoning Provincial Basic Research Projects (JYTMS20230098) and the 30 Project Fund of Shengjing Hospital (M0269).
These authors contributed equally: Jiashuo Yang, Yan Yu. Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China Jiashuo Yang, Jinlin Fan, Kunlong Hong, Naibo Zhang & Jian Zheng Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Yang, J., Yu, Y., Fan, J. et al.
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