CircFndc3b Mediates Exercise‐Induced Neuroprotection by Mitigating Microglial/Macrophage Pyroptosis via the ENO1/KLF2 Axis in Stroke Mice

Abstract Circular RNA (circRNA) plays a pivotal role in regulating neurological damage post‐ischemic stroke. Previous researches demonstrated that exercise mitigates neurological dysfunction after ischemic stroke, yet the specific contributions of circRNAs to exercise‐induced neuroprotection remain unclear. This study reveals that mmu_circ_0001113 (circFndc3b) is markedly downregulated in the penumbral cortex of a mouse model subjected to middle cerebral artery occlusion (MCAO). However, exercise increased circFndc3b expression in microglia/macrophages, alleviating pyroptosis, reducing infarct volume, and enhancing neurological recovery in MCAO mice. Mechanistically, circFndc3b interacted with Enolase 1 (ENO1), facilitating ENO1's binding to the 3' Untranslated Region (3'UTR) of Krüppel‐like Factor 2 (Klf2) mRNA, thereby stabilizing Klf2 mRNA and increasing its protein expression, which suppressed NOD‐like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome‐mediated microglial/macrophage pyroptosis. Additionally, circFndc3b enhanced ENO1's interaction with the 3′UTR of Fused in Sarcoma (FUS) mRNA, leading to increased FUS protein levels and promoting circFndc3b cyclization. These results suggest that circFndc3b mediates exercise‐induced anti‐pyroptotic effects via the ENO1/Klf2 axis, and a circFndc3b/ENO1/FUS positive feedback loop may potentiate exercise's neuroprotective effects. This study unveils a novel mechanism underlying exercise‐induced neuroprotection in ischemic stroke and positions circFndc3b as a promising therapeutic target for stroke management, mimicking the beneficial effects of exercise.