Targeting the glial-fibrotic scar microenvironment after spinal cord injury: From integrated protection to systematic regulation of regenerative balance.

Spinal cord injury (SCI) represents a severe neurological disorder characterized by complex pathophysiological cascades, frequently resulting in irreversible sensorimotor deficits. A hallmark of this condition is the dual-phase response of glial and fibrotic scars: initially, reactive astrocytes and fibroblast-like cells form protective barriers that limit inflammatory spread and stabilize tissue integrity, yet chronically, these scars transition into inhibitory structures through excessive deposition of chondroitin sulfate proteoglycans (CSPGs) and collagen-rich extracellular matrix (ECM), obstructing axonal regeneration. Critically, these scars operate within an integrated SCI scar microenvironment, where multiple cellular, molecular, and matrix components dynamically and coordinately modulate their reparative-to-pathological shift. This review systematically examines the spatiotemporal organization, cellular heterogeneity, and molecular drivers underlying scar duality. We evaluate bidirectional interactions between glial and fibrotic components and non-scar elements. Notably, the scar microenvironment serves as a pivotal regulatory hub that dictates the switch between the protective and inhibitory phenotypes of scars post-SCI. This work underscores the scar microenvironment's centrality in SCI pathology and advances the conceptual framework for developing precision therapies to overcome neuroregenerative failure. The Translational Potential of this Article: This review's spinal cord injury scar microenvironment theory delivers a transformative translational framework. It captures spatiotemporal crosstalk of cellular, molecular, and matrix components across injury phases, replacing fragmented single-target interventions. Representative translational strategies include artificial spinal cord ECM hydrogels, Induced Pluripotent Stem Cells (iPSCs) derived spinal cord organoid transplantation, exosome-mediated epigenetic regulation, among others, which are all aligned with pathological progression. Supported by international Phase I/II clinical trials targeting scar microenvironment components, this theory integrates basic research with clinical needs. It enables precision SCI therapy through coordinated intervention logic, accelerating the translation from symptomatic management to curative neural repair.