The IGF2BP3/circDock1/TCF21 axis relieves chronic cerebral ischemic injury by regulating neuronal ferroptosis

Ferroptosis, a form of cell death driven by iron and lipid damage, exacerbates brain injury during chronic cerebral ischemia. However, its precise regulatory mechanisms remain poorly understood. Here we show that the RNA-binding protein IGF2BP3 suppresses neuronal ferroptosis in mouse models of cerebral ischemia through a specific IGF2BP3/circRNA Dock1/TCF21 signaling axis. Mechanistically, IGF2BP3 binds to Alu elements of the Dock1 gene, promoting its reverse splicing into circRNA Dock1. We demonstrate that this circular RNA encodes a protein, DOCK1-704aa. Acting as a kinase, DOCK1-704aa directly binds and phosphorylates the transcription factor TCF21 at serine 116. Unphosphorylated TCF21 represses the transcription of major ferroptosis defense genes, Gpx4 and Fsp1 . However, DOCK1-704aa-mediated phosphorylation relieves this repression, thereby inhibiting ferroptosis and reducing ischemic brain damage. These findings reveal a precise post-transcriptional and post-translational network controlling neuronal survival during ischemic stress.