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These disorders, including postoperative delirium and sustained cognitive decline, significantly reduce patient quality of life and impose substantial burdens on healthcare systems. Despite extensive research, the underlying pathophysiological mechanisms remain inadequately understood, limiting the development of effective treatments. Increasing evidence highlights neuroinflammation as a central factor in PND, with microglia\u2014the resident immune cells of the central nervous system\u2014playing a key role in mediating inflammatory responses that lead to cognitive dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This review comprehensively analyzes the role of microglia in the pathogenesis of PND. It details key perioperative triggers of microglial activation, such as surgical stress, anesthesia, and systemic inflammation. The review further examines preclinical interventions aimed at modulating microglial function, including depletion strategies, polarization toward anti\u2010inflammatory phenotypes, and inhibition of inflammatory pathways like NF\u2010\u03baB and NLRP3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Preclinical studies demonstrate that dysregulated microglial activation results in excessive production of pro\u2010inflammatory cytokines, oxidative stress, and synaptic disruptions, which collectively contribute to neuronal injury and cognitive impairment. Interventions targeting microglial activation have shown efficacy in reducing neuroinflammation and preserving cognitive function in animal models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Targeting microglial activation represents a promising strategy for alleviating PND. However, challenges remain in clinical translation, necessitating advanced drug delivery platforms, personalized therapeutic approaches, and rigorous clinical validation. Advances in microglial modulation hold potential for improving postoperative cognitive outcomes and enhancing patient recovery.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70481","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T09:18:32Z","timestamp":1752830312000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Microglial Modulation as a Therapeutic Avenue for Perioperative Neurocognitive Disorders: Unveiling Pathophysiological Mechanisms and Clinical Implications"],"prefix":"10.1111","volume":"31","author":[{"given":"Xizhen","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology The Affiliated People's Hospital of Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The Second Affiliated Hospital, School 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