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

Sep 30, 2026

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Intracerebral hemorrhage (ICH) is a devastating stroke subtype marked by high morbidity and mortality. Beyond primary damage from blood extravasation, secondary injury from erythrocyte lysis and toxic degradation products amplifies inflammation, oxidative stress, and neuronal dysfunction. Enhancing endogenous hematoma resolution—through removal of erythrocytes and their byproducts—emerges as a promising therapeutic direction. This review organizes three core mechanisms: phagocytosis via TAM/CD36/TREM2-like axes, clearance of hemolytic products via hemoglobin-haptoglobin-CD163 and hemin-hemopexin-CD91, and glymphatic/meningeal lymphatic drainage, supported by pharmacological, genetic, and physical interventions.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Introduction

Rev. Neurol. 2025; 80(11): 46121 [https://doi.org/10.31083/RN46121](https://doi.org/10.31083/RN46121) Review Potential Therapeutic Targets and Emerging Strategies to Promote Hematoma Resolution in Intracerebral Hemorrhage Shuling Wan 1, Xunming Ji2, Ran Meng 1 , *, Min Li 1 , * 1Department of Neurology, Xuanwu Hospital Capital Medical University, 100053 Beijing, China 2Department of Neurosurgery, Xuanwu Hospital Capital Medical University, 100053 Beijing, China *Correspondence: [ranmeng2011@126.com](ranmeng2011@126.com) (Ran Meng); [812879698@qq.com](812879698@qq.com) (Min Li) Academic Editor: Angela Vidal-Jordana Submitted: 28 August 2025 Revised: 7 November 2025 Accepted: 17 November 2025 Published: 22 December 2025 Abstract 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 ofthe intracerebral hematoma, this review highlights promising therapeutic targets and strategies to overcome current clinical limitations and demonstrates significant translational potential. Keywords: intracerebral hemorrhage; hematoma absorption; novel therapy; phagocytosis; glymphatic system; meningeal lymphatic vessels Posibles Objetivos Terapéuticosy Estrategias Emergentes Para favorecer la Resolución del Hematoma en lasHemorragias Intracerebrales Resumen La hemorragia intracerebral (ICH, intracerebral hemorrhage) es un subtipo de accidente cerebrovascular devastador con una alta morbilidad y mortalidad. Más allá de la lesión primaria causada por la extravasación de sangre, la lesión secundaria provocada por la lisis de los eritrocitos y sus productos de degradación tóxicos exacerba la inflamación, el estrés oxidativoy el daño neuronal. Por ello, acelerar la resolución endógena del hematoma, que incluye eliminar los eritrocitos y sus subproductos, representa una estrategia terapéutica prometedora. Esta revisión describe sistemáticamente tres mecanismos clave de resolución del hematoma tras una ICH: (1) la eritrofagocitosis por parte de la microglía/macrófagos a través de los receptores TAM (Tyro3, Axl y Mertk), el grupo de diferenciación (CD, cluster of differentiation) 36, el receptor activador expresado en células mieloides 2 y el receptor de la proteína reguladora de señales α; (2) la eliminación de productos hemolíticos a través de los ejes hemoglobina-haptoglobina-CD163 y hemina-hemopexina-CD91; y (3) el drenaje glinfático y linfático meníngeo. Las intervenciones farmacológicas, genéticas y físicas dirigidas a estas vías han demostradosu potencial para mejorar la fagocitosis, favorecer la función glinfática y linfática meníngea, acelerar la resolución del hematoma y mejorar los resultados neurológicos en modelos de ICH. Al hacer uso de los mecanismos de eliminaciónintrínsecos del hematoma intracerebral, esta revisión destaca objetivos

FAQs

Why is hematoma resolution important in intracerebral hemorrhage?

ICH involves both primary injury from blood extravasation and secondary injury from erythrocyte lysis products. Accelerating endogenous hematoma clearance can improve recovery by mitigating downstream inflammatory and oxidative damage.

What are the main mechanisms of hematoma resolution discussed in the review?

The review highlights three mechanisms: erythrophagocytosis by microglia/macrophages, clearance of hemolytic products via hemoglobin-haptoglobin-CD163 and hemin-hemopexin-CD91 axes, and glymphatic plus meningeal lymphatic drainage.

What types of interventions have shown potential to enhance hematoma resolution?

Pharmacological, genetic, and physical interventions targeting these pathways have demonstrated potential to enhance phagocytosis, support glymphatic/meningeal lymphatic function, accelerate hematoma resolution, and improve neurological outcomes in ICH models.

Sep 30, 2026

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