Buyang Huanwu decoction promotes post-stroke white matter repair via TREM2-Dependent microglial phagocytosis and IGF1 secretion.

White matter injury (WMI) following ischemic stroke represents a critical pathological determinant of persistent neurological impairment, with current therapeutic options remaining limited. Buyang Huanwu Decoction (BYHWD), a time-honored formulation historically deployed in traditional Chinese medicine to address post-stroke sequelae, exhibits documented neuroprotective efficacy; nevertheless, its mechanistic actions governing post-ischemic white matter restoration and remyelination are yet to be fully deciphered. This study aimed to elucidate whether BYHWD facilitates post-ischemic white matter restoration via TREM2-dependent mechanisms. Transient middle cerebral artery occlusion (tMCAO) was induced in mice to model ischemic stroke. Neurological recovery was longitudinally assessed using standardized behavioral tests. Cerebral atrophy and histopathological damage were quantified through hematoxylin-eosin (H&E) and cresyl violet staining. Network pharmacology analysis predicted potential therapeutic targets and pathways, with subsequent validation performed via immunofluorescence techniques. White matter integrity was evaluated by magnetic resonance imaging (MRI) and Luxol fast blue (LFB) myelin staining. Western blotting analyzed striatal TREM2 expression and downstream signaling molecules. Microglial phagocytic activity was determined via immunofluorescence co-localization of myelin basic protein (MBP) with phagocytosis receptors AXL and CD11c. Additional immunofluorescence characterized microglial IGF1 secretion and oligodendrocyte IGF1R expression/proliferation. BYHWD markedly improved long-term neurological outcomes and mitigated white matter injury in tMCAO mice. Mechanistically, it appeared to enhance TREM2-dependent microglial phagocytosis of myelin debris and to promote microglial IGF1 secretion via activation of the TREM2-ERK1/2 signaling axis, which was associated with increased oligodendrocyte proliferation and remyelination. These findings indicate that BYHWD may facilitate post-stroke white matter repair by modulating TREM2-dependent microglia-oligodendrocyte interactions, supporting its potential as a therapeutic approach for TREM2-associated white matter injury.