摘要High mobility group box 1 is a dynamic nuclear protein that acts as a damage-associated molecular pattern when released from cells and plays key roles in neurodegenerative diseases.This review comprehensively analyzes the related post-translational modifications that affect the dual functions of high mobility group box 1 in neuroinflammation and neuronal survival,including acetylation,phosphorylation,oxidation,S-nitrosylation,lactylation,and ubiquitination.Post-translational modifications play critical regulatory roles in high mobility group box 1 subcellular localization,release processes and the specificity of receptor binding.In Alzheimer's disease,high mobility group box 1 exacerbates the disease through the Toll-like receptor 4/nuclear factor kappa B signaling pathway.Inhibition of high mobility group box 1 acetylation can alleviate neuroinflammation.Parkinson's disease models indicate that the S-nitrosylation of Cys106 is essential for the secretion of high mobility group box 1,which contributes to dopaminergic degeneration through the activation of microglia.In multiple sclerosis,high mobility group box 1 obstructs remyelination by inhibiting the maturation of oligodendrocytes and activating pro-inflammatory pathways.In contrast,high mobility group box 1 can maintain autophagy and DNA repair functions,suggesting its protective role.Therapeutic strategies targeting high mobility group box 1 show potential benefits.Glycyrrhizic acid inhibits disulfide-linked high mobility group box 1,SIRT activators suppress acetylation,and anti-high mobility group box 1 antibodies neutralize extracellular isoforms,thereby improving the results of preclinical studies.However,the diverse functions of high mobility group box 1 and the lack of post-translational modification-specific biomarkers present challenges for clinical translation.Future research should aim to create selective inhibitors that can cross the blood-brain barrier to target harmful forms of high mobility group box 1,and establish post-translational modification-based biomarkers for early detection.This review emphasizes that accurately targeting of high mobility group box 1 post-translational modifications in neurodegenerative diseases could be a new approach that can interrupt neuroinflammatory cascades while maintaining neuroprotective functions.