Potential Therapeutic Targets and Emerging Strategies to Promote Hematoma Resolution in Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating stroke subtype with high morbidity and mortality. Beyond primary injury from blood extravasation, secondary injury driven by erythrocyte lysis and its toxic degradation products exacerbates inflammation, oxidative stress, and neuronal damage. Accelerating endogenous hematoma resolution, including the removal of erythrocytes and their byproducts, represents a promising therapeutic strategy. This review systematically delineates three key mechanisms of hematoma resolution post-ICH: (1) erythrophagocytosis by microglia/macrophages through Tyro3, Axl, and Mertk (TAM) receptors, the cluster of differentiation (CD) 36 receptor, the triggering receptor expressed on myeloid cells 2, and the signal regulatory protein α receptor; (2) clearance of hemolytic products through the hemoglobin-haptoglobin-CD163 and hemin-hemopexin-CD91 axes; and (3) glymphatic and meningeal lymphatic drainage. Pharmacological, genetic, and physical interventions targeting these pathways have demonstrated potential to enhance phagocytosis, promote glymphatic and meningeal lymphatic function, accelerate hematoma resolution, and improve neurological outcomes in ICH models. By leveraging the intrinsic clearance mechanisms of the intracerebral hematoma, this review highlights promising therapeutic targets and strategies to overcome current clinical limitations and demonstrates significant translational potential.