{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T23:56:13Z","timestamp":1783468573048,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T00:00:00Z","timestamp":1746316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Liaoning Provincial Department of Education Research Foundation of China","award":["No. LJKZ0844"],"award-info":[{"award-number":["No. LJKZ0844"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent epidemiological studies have indicated that exposure to particulate matter with an aerodynamic diameter of 2.5 \u03bcm or less in the ambient air (PM2.5) is significantly associated with an elevated risk of developing Alzheimer\u2019s disease (AD) and its progression. Scorpion venom heat-resistant synthetic peptide (SVHRSP) exhibits anti-inflammatory and neuroprotective properties. However, the exact ways in which SVHRSP mitigates the progression of AD induced by PM2.5 are still unknown. Long non-coding RNA (lncRNA) plays a crucial role in various biological processes. Necroptosis, a form of programmed cell death, has garnered considerable attention in recent years. This study aims to investigate whether Lnc Gm16410 and neuronal necroptosis are involved in PM2.5-exacerbated AD progression and the mechanisms of SVHRSP in alleviating this process. Through the establishment of a PM2.5 exposure model in AD mice and an in vitro model, it was found that PM2.5 exposure could promote necroptosis and the down-regulation of Lnc Gm16410, thereby promoting the progression of AD. Behavioral tests showed that SVHRSP alleviated cognitive impairment in PM2.5-induced AD mice. WB, qRT-PCR, and other molecular biological assays indicate that Lnc Gm16410 regulates neuronal necroptosis under PM2.5 exposure via the p38 MAPK pathway. SVHRSP is a potential regulator of AD progression by regulating Lnc Gm16410 to alleviate PM2.5 exposure-induced necroptosis. These findings offer new insights into the mechanism through which PM2.5 exposure accelerates the progression of AD, examined from the perspective of LncRNA. Furthermore, we offer new targets for the treatment and prevention of AD following PM2.5 exposure by investigating the mechanism of action of SVHRSP in alleviating AD.<\/jats:p>","DOI":"10.3390\/ijms26094372","type":"journal-article","created":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T20:10:27Z","timestamp":1746389427000},"page":"4372","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Scorpion Venom Heat-Resistant Synthetic Peptide Alleviates Neuronal Necroptosis in Alzheimer\u2019s Disease Model by Regulating Lnc Gm6410 Under PM2.5 Exposure"],"prefix":"10.3390","volume":"26","author":[{"given":"Chuhao","family":"Qin","sequence":"first","affiliation":[{"name":"College of Medical Laboratory, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsheng","family":"Li","sequence":"additional","affiliation":[{"name":"College of Medical Laboratory, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Medical Laboratory, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze","family":"Yin","sequence":"additional","affiliation":[{"name":"College of Medical Laboratory, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9368-7339","authenticated-orcid":false,"given":"Fasheng","family":"Li","sequence":"additional","affiliation":[{"name":"College of Medical Laboratory, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3543","DOI":"10.1093\/eurheartj\/ehy481","article-title":"Effects of gaseous and solid constituents of air pollution on endothelial function","volume":"39","author":"Gori","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6034","DOI":"10.1172\/JCI137315","article-title":"Metabolic effects of air pollution exposure and reversibility","volume":"130","author":"Rajagopalan","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"n2561","DOI":"10.1136\/bmj.n2561","article-title":"Cut particulate air pollution, save lives","volume":"375","author":"Pereira","year":"2021","journal-title":"Bmj"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1001\/jamainternmed.2022.4696","article-title":"Association of Particulate Matter Exposure With Lung Function and Mortality Among Patients With Fibrotic Interstitial Lung Disease","volume":"182","author":"Goobie","year":"2022","journal-title":"JAMA Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1164\/rccm.202112-2668TR","article-title":"Mechanistic Insights into the Impact of Air Pollution on Pneumococcal Pathogenesis and Transmission","volume":"206","author":"Beentjes","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107706","DOI":"10.1016\/j.envint.2022.107706","article-title":"Diesel exhaust PM2.5 greatly deteriorates fibrosis process in pre-existing pulmonary fibrosis via ferroptosis","volume":"171","author":"Yue","year":"2023","journal-title":"Environ. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1093\/eurheartj\/ehab892","article-title":"European Society of Cardiology: Cardiovascular disease statistics 2021","volume":"43","author":"Timmis","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/s41583-022-00672-8","article-title":"Neurotoxic effects of air pollution: An urgent public health concern","volume":"24","author":"Sobolewski","year":"2023","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_10","unstructured":"GBD 2019 Dementia Forecasting Collaborators (2022). Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health, 7, e105\u2013e125."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Twarowski, B., and Herbet, M. (2023). Inflammatory Processes in Alzheimer\u2019s Disease-Pathomechanism, Diagnosis and Treatment: A Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076518"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/j.neuron.2022.03.004","article-title":"ApoE Cascade Hypothesis in the pathogenesis of Alzheimer\u2019s disease and related dementias","volume":"110","author":"Martens","year":"2022","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1016\/j.neuron.2024.02.017","article-title":"P-tau217 correlates with neurodegeneration in Alzheimer\u2019s disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy","volume":"112","author":"Zhang","year":"2024","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.neuron.2024.10.029","article-title":"Integrative pathway analysis across humans and 3D cellular models identifies the p38 MAPK-MK2 axis as a therapeutic target for Alzheimer\u2019s disease","volume":"113","author":"Kwak","year":"2025","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/s41582-022-00714-w","article-title":"Gene-environment interactions in Alzheimer disease: The emerging role of epigenetics","volume":"18","author":"Migliore","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e557","DOI":"10.1016\/S2542-5196(20)30227-8","article-title":"Long-term effects of PM(2\u00b75) on neurological disorders in the American Medicare population: A longitudinal cohort study","volume":"4","author":"Shi","year":"2020","journal-title":"Lancet Planet Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial","volume":"330","author":"Sims","year":"2023","journal-title":"J. Am. Med. Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/s41582-023-00883-2","article-title":"Tau-targeting therapies for Alzheimer disease: Current status and future directions","volume":"19","author":"Congdon","year":"2023","journal-title":"Nat. Rev. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5143","DOI":"10.1002\/alz.13859","article-title":"Revised criteria for diagnosis and staging of Alzheimer\u2019s disease: Alzheimer\u2019s Association Workgroup","volume":"20","author":"Jack","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/s41423-020-00630-3","article-title":"Necroptosis, pyroptosis and apoptosis: An intricate game of cell death","volume":"18","author":"Bertheloot","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.molcel.2023.11.040","article-title":"The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death","volume":"84","author":"Ai","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.molcel.2023.12.041","article-title":"PARP5A and RNF146 phase separation restrains RIPK1-dependent necroptosis","volume":"84","author":"Hou","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1136\/ard-2023-224491","article-title":"Expression of HIF1\u03b1 in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery","volume":"83","author":"Lyu","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1016\/j.ccell.2024.10.014","article-title":"Interleukin-1\u03b1 release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity","volume":"42","author":"Li","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1084\/jem.20182351","article-title":"A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis","volume":"216","author":"Takezaki","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.freeradbiomed.2023.06.017","article-title":"PM2.5 contributed to pulmonary epithelial senescence and ferroptosis by regulating USP3-SIRT3-P53 axis","volume":"205","author":"Li","year":"2023","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Fan, X., Dong, T., Yan, K., Ci, X., and Peng, L. (2023). PM2.5 increases susceptibility to acute exacerbation of COPD via NOX4\/Nrf2 redox imbalance-mediated mitophagy. Redox Biol., 59.","DOI":"10.1016\/j.redox.2022.102587"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"135726","DOI":"10.1016\/j.chemosphere.2022.135726","article-title":"Wood smoke particulate matter (WSPM2.5) induces pyroptosis through both Caspase-1\/IL-1\u03b2\/IL-18 and ATP\/P2Y-dependent mechanisms in human bronchial epithelial cells","volume":"307","author":"Fu","year":"2022","journal-title":"Chemosphere"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/s41580-022-00566-8","article-title":"Long non-coding RNAs: Definitions, functions, challenges and recommendations","volume":"24","author":"Mattick","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41580-023-00694-9","article-title":"Transcription regulation by long non-coding RNAs: Mechanisms and disease relevance","volume":"25","author":"Ferrer","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1016\/j.molcel.2022.05.027","article-title":"Integrated lncRNA function upon genomic and epigenomic regulation","volume":"82","author":"Herman","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1016\/j.cmet.2021.11.011","article-title":"NEAT1 is essential for metabolic changes that promote breast cancer growth and metastasis","volume":"33","author":"Park","year":"2021","journal-title":"Cell Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e153563","DOI":"10.1172\/JCI153563","article-title":"A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression","volume":"132","author":"Du","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e169112","DOI":"10.1172\/JCI169112","article-title":"The long noncoding RNA CARDINAL attenuates cardiac hypertrophy by modulating protein translation","volume":"134","author":"He","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Xu, J., Xu, H., Ma, K., Wang, Y., Niu, B., Zhang, L., and Li, F. (2021). lncRNA Gm16410 Mediates PM2.5-Induced Macrophage Activation via PI3K\/AKT Pathway. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.618045"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"111327","DOI":"10.1016\/j.ecoenv.2020.111327","article-title":"LncRNA Gm16410 regulates PM(2.5)-induced lung Endothelial-Mesenchymal Transition via the TGF-\u03b21\/Smad3\/p-Smad3 pathway","volume":"205","author":"Ma","year":"2020","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"176704","DOI":"10.1016\/j.ejphar.2024.176704","article-title":"Scorpion venom heat-resistant synthesized peptide ameliorates epileptic seizures and imparts neuroprotection in rats mediated by NMDA receptors","volume":"978","author":"Sui","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"106978","DOI":"10.1016\/j.phrs.2023.106978","article-title":"Scorpion venom peptides: Molecular diversity, structural characteristics, and therapeutic use from channelopathies to viral infections and cancers","volume":"197","author":"Xia","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.1111\/bph.15502","article-title":"Scorpion venom heat-resistant synthesized peptide ameliorates 6-OHDA-induced neurotoxicity and neuroinflammation: Likely role of Na(v) 1.6 inhibition in microglia","volume":"178","author":"Li","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.freeradbiomed.2022.06.241","article-title":"A novel synthetic peptide SVHRSP attenuates dopaminergic neurodegeneration by inhibiting NADPH oxidase-mediated neuroinflammation in experimental models of Parkinson\u2019s disease","volume":"188","author":"Zhang","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, Y., Wang, Z., Guo, S., Li, Q., Kong, Y., Sui, A., Ma, J., Lu, L., Zhao, J., and Li, S. (2024). SVHRSP Alleviates Age-Related Cognitive Deficiency by Reducing Oxidative Stress and Neuroinflammation. Antioxidants, 13.","DOI":"10.3390\/antiox13060628"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"175328","DOI":"10.1016\/j.scitotenv.2024.175328","article-title":"CircCDR1as orchestrates the advancement of asthma triggered by PM(2.5) through the modulation of ferroptosis","volume":"950","author":"Cheng","year":"2024","journal-title":"Sci. Total Environ."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"118320","DOI":"10.1016\/j.envpol.2021.118320","article-title":"PM2.5 exposure in association with AD-related neuropathology and cognitive outcomes","volume":"292","author":"Thiankhaw","year":"2022","journal-title":"Environ. Pollut."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e172826","DOI":"10.1172\/JCI172826","article-title":"MAPK phosphatase 1 inhibition of p38\u03b1 within lung myofibroblasts is essential for spontaneous fibrosis resolution","volume":"134","author":"Fortier","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"eadn5993","DOI":"10.1126\/sciadv.adn5993","article-title":"Remodeling p38 signaling in muscle controls locomotor activity via IL-15","volume":"10","author":"Folgueira","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1093\/toxres\/tfad064","article-title":"Scorpion venom heat-resistant peptide alleviates mitochondrial dynamics imbalance induced by PM(2.5) exposure by downregulating the PGC-1\u03b1\/SIRT3 signaling pathway","volume":"12","author":"Huang","year":"2023","journal-title":"Toxicol. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4080","DOI":"10.1002\/alz.13814","article-title":"Long-term exposure to air pollution and road traffic noise and incidence of dementia in the Danish Nurse Cohort","volume":"20","author":"Tuffier","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref_49","first-page":"100213","article-title":"PM(2.5) exposure associated with microbiota gut-brain axis: Multi-omics mechanistic implications from the BAPE study","volume":"3","author":"Li","year":"2022","journal-title":"Innovation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e2101251","DOI":"10.1002\/advs.202101251","article-title":"An Air Particulate Pollutant Induces Neuroinflammation and Neurodegeneration in Human Brain Models","volume":"8","author":"Kang","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.ecoenv.2019.02.086","article-title":"A review of the possible associations between ambient PM2.5 exposures and the development of Alzheimer\u2019s disease","volume":"174","author":"Shou","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"100005","DOI":"10.1124\/pharmrev.123.000823","article-title":"Ferroptosis and pathogenesis of neuritic plaques in Alzheimer\u2019s Disease","volume":"77","author":"Streit","year":"2025","journal-title":"Pharmacol. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00401-022-02528-y","article-title":"Pyroptosis in Alzheimer\u2019s disease: Cell type-specific activation in microglia, astrocytes and neurons","volume":"145","author":"Moonen","year":"2023","journal-title":"Acta. Neuropathol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12223","DOI":"10.7150\/thno.50992","article-title":"Virus-induced p38 MAPK activation facilitates viral infection","volume":"10","author":"Cheng","year":"2020","journal-title":"Theranostics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4372\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:26:58Z","timestamp":1760030818000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4372"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,4]]},"references-count":54,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094372"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094372","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,4]]}}}