Astrocyte-Microglia Crosstalk in Post-Hemorrhagic Neurovascular Microenvironment: Mechanistic Nodes, Cross-Stroke Comparisons, and Therapeutic Reprogramming.

BACKGROUND: Intracerebral hemorrhage (ICH) produces a rapidly evolving and spatially heterogeneous neurovascular microenvironment in which secondary injury is shaped not only by hematoma volume and location, but also by the interaction of blood-derived toxins, blood-brain barrier disruption, edema, oxidative stress, protease activity, and glial responses. Increasing evidence suggests that these processes are better understood as dynamic network events rather than isolated inflammatory pathways. MAIN BODY: This review applies a network-centered framework to astrocyte-microglia coupling, viewing it as a critical control layer that may either support injury containment and hematoma resolution or drive persistent neurotoxicity and failed repair. Comparisons with ischemic stroke are used to distinguish shared inflammatory modules from hemorrhage-specific drivers, including heme, hemoglobin, iron overload, thrombin, fibrinogen, and clot-associated protease signaling. Integrating findings from single-cell and spatially resolved studies, the review summarizes the temporal and spatial organization of post-hemorrhagic microenvironment remodeling and discusses astrocyte-dependent regulation of barrier function, edema dynamics, immunometabolism, redox buffering, and synaptic homeostasis. It also examines how astrocyte-derived cues influence microglial state transitions through danger sensing, inflammasome signaling, cyclic GMP-AMP synthase-stimulator of interferon (IFN) genes signaling, phagocytic containment, iron-handling programs, complement-mediated synaptic vulnerability, and interaction with infiltrating myeloid cells. Recurring astrocyte-microglia network motifs are further evaluated as therapeutic control points, with emphasis on how lesion stage and spatial compartmentalization shape intervention windows for purinergic, chemokine, cytokine, IFN, complement-coagulation, and lipid/iron signaling pathways. Translational priorities, limitations, and therapeutic opportunities are discussed across hematoma-toxicity reduction, barrier and edema repair, network reprogramming, and regenerative microenvironment shaping. CONCLUSION: Meaningful improvement in ICH outcome will likely depend on biomarker-guided and stage-specific reprogramming of astrocyte-microglia network dynamics to restore microenvironmental balance, rather than on nonspecific suppression of neuroinflammation.