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Vitamin B12 attenuates post-ischemic brain fibrotic remodeling and suppresses MAPK1 signaling in male rats
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DOI：10.1016/j.brainresbull.2026.111847.png)
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Abstract
En 中文
Ischemic stroke (IS) is a major global cause of mortality and disability, with fibrotic scar formation during disease progression markedly restricting neurological recovery. Vitamin B12 (cobalamin) has been shown to improve short-term stroke outcomes; however, its regulatory role in long-term fibrotic remodeling, particularly its capacity to modulate specific molecular pathways, is incompletely understood. The present study integrated network pharmacology with drug-target Mendelian randomization (MR) to identify pivotal vitamin B12-related targets involved in post-ischemic fibrosis, yielding three candidate genes-ALDH2, CD40, and mitogen-activated protein kinase 1 (MAPK1). These targets were subsequently validated through molecular docking, molecular dynamics simulation, nomogram prediction, and in vivo experiments using the middle cerebral artery occlusion/ reperfusion (MCAO/R) rat model. The findings suggested that ALDH2 and CD40 act as protective factors, whereas MAPK1 serves as a risk-susceptible driver of post-ischemic fibrotic remodeling. Reverse MR emphasized MAPK1 as the most influential contributor to disease progression among these targets. In subacute MCAO/R male rats, vitamin B12 administration markedly suppressed MAPK1 expression, attenuated the expression of key fibrosis indicators (fibronectin, type I collagen, and alpha-smooth muscle actin), and improved motor recovery. Mechanistic analyses suggest that vitamin B12 may limit fibrotic scar deposition by coordinating a metabolism-immune-matrix regulatory network centered on MAPK1. These results provide a robust theoretical foundation for applying vitamin B12-based strategies to counteract post-ischemic fibrosis and establish MAPK1 as a promising therapeutic target for enhancing long-term neurological recovery in ischemic stroke.
Keywords:
Vitamin B12
Ischemic stroke
Fibrosis
Mendelian randomization
Network pharmacology
MAPK1
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