This review synthesizes evidence that redox- and modification-dependent extracellular HMGB1 drives neuroinflammation via TLR4/RAGE/CXCR4 and downstream NF-κB/MAPK/JAK-STAT/inflammasome pathways, links HMGB1 dysregulation to Parkinson's disease among other CNS disorders, and summarizes preclinical…

It highlights HMGB1 as a mechanistically actionable inflammatory node with multiple druggable approaches and existing preclinical tools that could be leveraged for PD neuroprotection and target validation, but cautions that overcoming BBB delivery, specificity, and clinical validation is essential…

High mobility group box 1 (HMGB1) has emerged as a central inflammatory mediator linking cellular stress and tissue injury to sustained neuroinflammation in the central nervous system. Although originally characterized as a nuclear chromatin-binding protein, HMGB1 acquires potent pro-inflammatory activity following cytoplasmic translocation and extracellular release, where it functions as a damage-associated molecular pattern. The inflammatory actions of HMGB1 are regulated by its redox state and post-translational modifications, which determine receptor engagement and downstream signaling. Extracellular HMGB1 interacts with pattern-recognition receptors including TLR4/MD-2, the receptor for advanced glycation end products (RAGE), CXCR4, and nucleic acid-sensing Toll-like receptors, leading to activation of NF-κB, MAPK, JAK/STAT, and inflammasome pathways. These cascades amplify cytokine production, glial activation, oxidative stress, blood-brain barrier disruption, and neuronal dysfunction. Dysregulated HMGB1 signaling has been implicated in acute and chronic neurological disorders, including ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy. From a pharmacological perspective, HMGB1 has emerged as a potential therapeutic target, although most supporting evidence currently comes from preclinical studies and further clinical validation is required. Several strategies aimed at attenuating HMGB1-driven inflammation-such as neutralizing antibodies, direct HMGB1 inhibitors including glycyrrhizin, TLR4 and RAGE antagonists, natural anti-inflammatory compounds, and nanotechnology-based delivery systems-have demonstrated beneficial effects in experimental and preclinical models, but clinical validation remains limited. However, clinical translation remains limited by poor blood-brain barrier penetration, insufficient redox specificity, receptor redundancy, and a lack of well-designed human trials. This review summarizes current knowledge on HMGB1 biology, disease relevance, and therapeutic targeting, and highlights key challenges and future directions for HMGB1-based anti-inflammatory therapies in neuroinflammatory disorders.