Sunitinib attenuates secondary injury via the regulation of peri-hematomal microglia at the acute phase of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a highly fatal stroke subtype with limited treatment options, where pathological activation of peri-hematomal microglia drives acute secondary injury. Colony-stimulating factor 1 receptor (CSF-1R), highly expressed in microglia, is a potential therapeutic target. This study evaluated the effects of short-term administration of sunitinib, a clinically used CSF-1R inhibitor, in a collagenase-induced mouse ICH model and an in vitro hemoglobin (Hb)-treated BV2 microglial model. Sunitinib significantly improved motor functions, reduced myelin damage, and attenuated microglial activation and neuroinflammation in peri-hematomal tissue. RNA sequencing revealed that sunitinib might modulate lipid metabolism, phagocytosis, and immune response. In BV2 cells, sunitinib inhibited Hb-induced lipid droplet accumulation, phagocytic reduction, and pro-inflammatory cytokine production, effects mirrored by CSF-1R knockdown. These findings suggest that sunitinib alleviates acute ICH injury by modulating microglial functions, likely through inhibition of the CSF-1R axis, supporting its potential repurposing for central nervous system disorders like ICH.