CircAbcc1-encoded ABCC1-677aa modulates DLX1 to suppress ferroptosis in chronic cerebral ischemia

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. A circular RNA, circAbcc1, protects neurons from ferroptosis during chronic cerebral ischemia by encoding the protein ABCC1-677aa. This protein relieves repression of anti-ferroptotic genes, reducing neuronal damage and highlighting the circAbcc1-DLX1 pathway as a therapeutic target.