Vitamin B12 drives reparative fibroblast remodeling and functional recovery after ischemic stroke via epigenetic activation of RUNX2.

Ischemic stroke remains a major cause of long-term neurological disability, and effective strategies that promote brain repair during the subacute phase are limited. Here, using a clinical cohort of patients with acute ischemic stroke, adult male C57BL/6J mouse models, and complementary in vitro fibroblast models, we identify vitamin B12 as a metabolic regulator of post-ischemic reparative remodeling and functional recovery. Vitamin B12 deficiency was associated with greater stroke severity, impaired neurological recovery, and weakened reparative fibrotic remodeling, whereas vitamin B12 supplementation under physiological nutritional conditions improved neurological recovery and enhanced reparative fibrotic remodeling. Mechanistically, vitamin B12 restored metabolic homeostasis in fibroblasts, increased intracellular acetyl-CoA availability, enhanced H3K27 acetylation, upregulated RUNX2 expression, enhanced RUNX2-p300 interaction, and activated RUNX2-dependent fibroblast programs. RUNX2 suppression or pharmacological inhibition of histone acetylation attenuated fibroblast activation and blunted the pro-repair effects of vitamin B12. Moreover, RUNX2 overexpression preferentially targeting fibroblast-associated cells improved defective reparative remodeling in vitamin B12-deficient mice. These findings identify a vitamin B12-dependent metabolic and epigenetic mechanism that activates RUNX2-associated fibroblast responses and supports subacute brain repair after ischemic stroke.