PARProceedings of Anticancer Research2208-35452208-3553Bio-Byword Scientific Publishing Pty. Ltd.10.26689/par.v10i4.15863ArticleResearch Progress on the Role of PKM2 in Perioperative Neurocognitive Disorders in Elderly Patientshttps://artdesignp.com/journal/PAR/10/4/10.26689/par.v10i4.15863LiQianyu,LiangJie20261042026-08-12Perioperative Neurocognitive Disorders (PND) are common postoperative complications affecting cognitive and behavioral function in elderly patients, significantly impacting recovery quality. Its pathogenesis is closely linked to an imbalance in cerebral metabolic-immune homeostasis. Recent studies have identified the key metabolic and immune enzyme, Pyruvate Kinase M2 (PKM2), as a participant in the initiation and progression of PND. Surgical trauma and anesthesia can upregulate PKM2 via signaling pathways such as HMGB1, TLR4, and HIF-1α, promoting its acetylation, dimerization, and nuclear translocation. Subsequently, activated PKM2 enhances oxidative stress and recruits NLRPs to drive neuroinflammation and synaptic plasticity decline, leading to postoperative cognitive dysfunction. These cascading changes, to a certain extent, affect postoperative neurological recovery. Mouse model studies have revealed therapeutic strategies targeting PKM2. This review summarizes the mechanisms by which PKM2 influences cognitive and behavioral function through the regulation of neuroinflammation and energy metabolism disorders, and discusses precise brain protection strategies targeting PKM2, offering new insights for the prevention and treatment of PND.

Evered L, Silbert B, Knopman DS, et al., 2018, Recommendations for the Nomenclature of Cognitive Change Associated With Anaesthesia and Surgery-2018. Anesthesiology, 129(5): 872–879.

Liu XH, Kang L, Zhu ML, 2023, Guidelines for Frailty Assessment and Management in Elderly Patients. Chinese Journal of Geriatrics, 42(1): 13–19.

Li J, Yang L, Qin W, et al., 2022, Pyruvate Kinase M2 in Neurodegeneration and Neuroinflammation. Nature Reviews Neuroscience, 23(12): 857–873.

Zhou HY, Wang FR, Luo WF, 2023, Research Progress on Neuroinflammatory Mechanisms of Perioperative Neurocognitive Disorders. Chinese Journal of Behavioral Medicine and Brain Science, 32(4): 375–380.

Yang W, Lu Z, 2023, Regulation and Function of Pyruvate Kinase M2 in Cancer and Inflammation. Trends in Biochemical Sciences, 48(7): 625–638.

Dayton TL, Jacks T, Vander Heiden MG, 2023, PKM2 Isoform-Specific Functions in Cellular Metabolism. EMBO Journal, 42(10): e113456.

Wang Y, Liu T, Yang N, et al., 2023, PKM2-Dependent Synaptic Plasticity Regulation. Neuron, 111(7): 1123–1135.

Li J, Chen Y, Wang X, et al., 2023, Propofol Attenuates Neuroinflammation via ROS Scavenging. Metabolism, 148: 155689.

Zhang Y, Liu X, Wang Z, et al., 2023, PKM2-MMP9 Axis in BBB Regulation. Nature Neuroscience, 26(11): 1583–1596.

Zhang Z, Qin P, Li J, et al., 2023, PKM2 in Neuronal Energy Homeostasis. Journal of Clinical Investigation, 133(9): e167892.

Wang Y, Liu Y, Zhang X, et al., 2023, CSF Biomarkers in POCD Patients. Annals of Neurology, 93(4): 789–801.

Wang Y, Liu T, Yang N, et al., 2023, Surgical Stress and PKM2 Expression in Hippocampal Microglia: Role of HMGB1-TLR4-NF-κB Signaling. Annals of Surgery, 277(5): e1024–e1031.

Zhang Q, Li R, Chen S, et al., 2021, Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Mice. Molecular Medicine, 27: 102.

Sadasivan S, et al., 2023, Sevoflurane-Induced Mitochondrial Dysfunction Promotes PKM2 Nuclear Translocation. Anesthesiology, 139(5): 634–648.

Shen Y, Jiang Y, Zhang Y, et al., 2023, Surgical Stress Induces Lactate-Mediated Microglial Activation and Cognitive Decline Through NLRP3 Inflammasome. Aging Cell, 22(5): e13822.

Li J, Chen Y, Zhang X, et al., 2023, PKM2-Mediated Microglial Activation. Nature Neuroscience, 26(5): 678–690.

Lin D, Wang S, Liu F, et al., 2022, Propofol Attenuates Neuroinflammation by Inhibiting the ROS/HIF-1α Pathway in Microglia. Journal of Neuroinflammation, 19(1): 148.

Li Y, Zhang Y, Wang X, et al., 2023, Propofol Maintains Pyruvate Kinase M2 Activity by Inhibiting Reactive Oxygen Species-Mediated Degradation. British Journal of Anaesthesia, 131(1): e45–e54.

Li Y, Chen J, Xu Y, 2022, Current Status and Prospects of Biomarkers for Postoperative Delirium. Chinese Journal of Neuromedicine, 21(8): 843–849.

Zhang Q, Liu R, Wang Y, et al., 2024, PKM2 S-Palmitoylation Mediates Microglial Metabolic Reprogramming in Neurodegenerative Disorders. Cell Metabolism, 36(1): 156–170.

Zhou Y, et al., 2023, Lactate Accumulation Impairs Synaptic Plasticity via MMP-9 Activation. Nature Communications, 14: 5123.

Jiang Y, et al., 2023, TEPP-46 Stabilizes PKM2 Tetramers to Suppress Neuroinflammation. Cell Reports, 42(5): 112456.

Zhang H, Liu R, Yang W, et al., 2023, Nose-to-Brain Delivery of PKM2 Inhibitors. ACS Nano, 17: 3785–3798.

Wang D, Chen Y, Liu R, et al., 2020, Mitochondrial Dysfunction Mediates Hepatotoxicity of PKM2 Modulators. Toxicological Sciences, 177(2): 347–359.

Kulkarni JA, et al., 2023, Brain-Targeted Lipid Nanoparticles for RNA Delivery to Microglia. Advanced Drug Delivery Reviews, 192: 114644.

Zhang Y, Wang H, Li J, et al., 2023, Real-Time Intraoperative Monitoring of Metabolic Biomarkers Using SERS Nanoprobes. Nature Biomedical Engineering, 7: 456–468.

Qin Z, et al., 2023, Surface-Enhanced Raman Spectroscopy (SERS) for In Vivo Biosensing: Towards Intraoperative Monitoring. Nature Reviews Bioengineering, 1(2): 1–15.

Zhao Y, Zhou X, Wu W, 2022, Current Research Status of the Impact of Comorbidities on Postoperative Cognitive Function in Elderly Surgical Patients. International Journal of Anesthesiology and Resuscitation, 43(6): 456–461.