{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T12:49:44Z","timestamp":1785934184986,"version":"3.56.0"},"reference-count":77,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"This work was supported by the Major Program of National Natural Science Foundation of China","award":["No. 82293651"],"award-info":[{"award-number":["No. 82293651"]}]},{"name":"the Key Program of National Natural Science Foundation of China","award":["Grant No. 82130055"],"award-info":[{"award-number":["Grant No. 82130055"]}]},{"name":"Science and Technology Research Project of Colleges and Universities in Hebei Province","award":["Grant No. ZD2022132"],"award-info":[{"award-number":["Grant No. ZD2022132"]}]},{"name":"Open Project of the Key Laboratory of Forensic Pathology of the Ministry of Public Security","award":["Grant No. GAFYBL202303"],"award-info":[{"award-number":["Grant No. GAFYBL202303"]}]},{"name":"Shanghai Key Laboratory of Forensic Medicine and Key Laboratory of Forensic Science, Ministry of Justice","award":["[Grant No. KF202404]"],"award-info":[{"award-number":["[Grant No. KF202404]"]}]},{"name":"the Natural Science Foundation of Hebei Province","award":["(No.:H2024206002)"],"award-info":[{"award-number":["(No.:H2024206002)"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Mol Biol Lett"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Abnormal climate change seriously endangers the safety of outdoor work and life, often causing hypothermia-induced coma or death. As the underlying mechanism has not been fully elucidated, a targeted treatment for hypothermia-triggered neuronal injury and forensic pathology indicators of fatal hypothermia are lacking. Herein, we aimed to explore hypothermia-induced changes in gene expression and metabolite profiles of cerebral cortical tissues to elucidate the mechanism of hypothermia-promoted necroptosis of cerebral cortical neurons. Flow cytometry and fluoro-jade C staining showed that low temperature caused necroptosis of cerebral cortical neurons. Transcriptomics identified 244 differential genes between hypothermia-exposed cortical tissue and control tissue. These genes were enriched in tumor necrosis factor (TNF)-\u03b1 and nuclear factor (NF)-kappa B signaling pathways, as revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Broadly targeted metabolomics identified 49 differential metabolites with significant differences. <jats:italic>N<\/jats:italic>-alpha-acetyl-L-arginine, argininosuccinic acid, glutaric acid, and other ornithine cycle-associated metabolites were significantly reduced in the hypothermia-exposed cortical tissue, driving fumaric acid reduction in the tricarboxylic acid (TCA) cycle. In addition, KEGG enrichment analysis showed significant changes in the TCA cycle pathway. A combined transcriptomic and metabolomic analysis uncovered that hypothermia induced oxidative stress through NF-\u03baB activation, caused mitochondrial damage, impaired the ornithine cycle, and, ultimately, induced neuronal necroptosis. Pharmacological inhibition of NF-\u03baB by the SC75741 inhibitor effectively ameliorated hypothermia-triggered necroptosis. In conclusion, our results suggest that the NF-\u03baB transcription factor is a potential marker of hypothermia-induced neuronal necroptosis in the mouse cerebral cortex. In addition, our findings indicate the mechanism of necroptosis in cerebral cortical neurons caused by low temperature, which is beneficial for our understanding of hypothermia-induced coma and death.<\/jats:p>","DOI":"10.1186\/s11658-025-00772-0","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T19:36:04Z","timestamp":1753126564000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Integrated transcriptomics and metabolomics confirms the oxidative stress mechanism of hypothermia-induced neuronal necroptosis"],"prefix":"10.1186","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7434-9678","authenticated-orcid":false,"given":"Song-Jun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Long","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Tong","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Rui","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Jing","family":"Sha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Cong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"772_CR1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k4306","volume":"363","author":"R Chen","year":"2018","unstructured":"Chen R, Yin P, Wang L, Liu C, Niu Y, Wang W, et al. Association between ambient temperature and mortality risk and burden: time series study in 272 main Chinese cities. BMJ. 2018;363: k4306.","journal-title":"BMJ"},{"issue":"9991","key":"772_CR2","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/S0140-6736(14)62114-0","volume":"386","author":"A Gasparrini","year":"2015","unstructured":"Gasparrini A, Guo Y, Hashizume M, Lavigne E, Zanobetti A, Schwartz J, et al. Mortality risk attributable to high and low ambient temperature: a multicountry observational study. Lancet. 2015;386(9991):369\u201375.","journal-title":"Lancet"},{"key":"772_CR3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.autneu.2016.01.001","volume":"196","author":"WP Cheshire Jr","year":"2016","unstructured":"Cheshire WP Jr. Thermoregulatory disorders and illness related to heat and cold stress. Auton Neurosci. 2016;196:91\u2013104.","journal-title":"Auton Neurosci"},{"issue":"6","key":"772_CR4","first-page":"141","volume":"64","author":"J Meiman","year":"2015","unstructured":"Meiman J, Anderson H, Tomasallo C. Centers for Disease Control and Prevention (CDC) Hypothermia-related deaths\u2013Wisconsin, 2014, and United States, 2003\u20132013. MMWR Morb Mortal Wkly Rep. 2015;64(6):141\u20133.","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"4","key":"772_CR5","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1007\/s00414-014-0977-1","volume":"128","author":"C Palmiere","year":"2014","unstructured":"Palmiere C, Teresi\u0144ski G, Hejna P. Postmortem diagnosis of hypothermia. Int J Legal Med. 2014;128(4):607\u201314.","journal-title":"Int J Legal Med"},{"issue":"3","key":"772_CR6","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1007\/s11739-009-0228-5","volume":"4","author":"C Caroselli","year":"2009","unstructured":"Caroselli C, Gabrieli A, Pisani A, Bruno G. Hypothermia: an under-estimated risk. Intern Emerg Med. 2009;4(3):227\u201330.","journal-title":"Intern Emerg Med"},{"key":"772_CR7","first-page":"3","volume-title":"Forensic Pathology Reviews, 5","author":"B Madea","year":"2008","unstructured":"Madea B, Tsokos M, Preu\u00df J. Death due to hypothermia, morphological finding their pathogenesis and diagnostic value. In: Tsokos M, editor. Forensic Pathology Reviews, 5. Totowa, NJ: Humana Press; 2008. p. 3\u201321."},{"issue":"3","key":"772_CR8","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1007\/s00414-012-0677-7","volume":"126","author":"P Hejna","year":"2012","unstructured":"Hejna P, Z\u00e1topkov\u00e1 L, Tsokos M. The diagnostic value of synovial membrane hemorrhage and bloody discoloration of synovial fluid (\u201cinner knee sign\u201d) in autopsy cases of fatal hypothermia. Int J Legal Med. 2012;126(3):415\u20139.","journal-title":"Int J Legal Med"},{"issue":"1\u20133","key":"772_CR9","doi-asserted-by":"publisher","first-page":"e82","DOI":"10.1016\/j.forsciint.2010.08.018","volume":"206","author":"C Zhou","year":"2011","unstructured":"Zhou C, Byard RW. Armanni-Ebstein phenomenon and hypothermia. Forensic Sci Int. 2011;206(1\u20133):e82\u20134.","journal-title":"Forensic Sci Int"},{"issue":"2\u20133","key":"772_CR10","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.forsciint.2007.09.017","volume":"176","author":"J Preuss","year":"2008","unstructured":"Preuss J, Dettmeyer R, Poster S, Lignitz E, Madea B. The expression of heat shock protein 70 in kidneys in cases of death due to hypothermia. Forensic Sci Int. 2008;176(2\u20133):248\u201352.","journal-title":"Forensic Sci Int"},{"issue":"12","key":"772_CR11","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1093\/qjmed\/95.12.775","volume":"95","author":"ML Mallet","year":"2002","unstructured":"Mallet ML. Pathophysiology of accidental hypothermia. QJM. 2002;95(12):775\u201385.","journal-title":"QJM"},{"key":"772_CR12","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.autneu.2016.02.009","volume":"196","author":"JW Castellani","year":"2016","unstructured":"Castellani JW, Young AJ. Human physiological responses to cold exposure: acute responses and acclimatization to prolonged exposure. Auton Neurosci. 2016;196:63\u201374.","journal-title":"Auton Neurosci"},{"key":"772_CR13","first-page":"54","volume":"87","author":"II Jeican","year":"2014","unstructured":"Jeican II. The pathophysiological mechanisms of the onset of death through accidental hypothermia and the presentation of \u201cThe Little Match Girl\u201d case. Clujul Med. 2014;87:54\u201360.","journal-title":"Clujul Med"},{"issue":"3","key":"772_CR14","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1097\/PAF.0000000000000484","volume":"40","author":"B Morleo","year":"2019","unstructured":"Morleo B, Teresinski G, Rousseau G, Tse R, Tettamanti C, Augsburger M, et al. Biomarkers of cerebral damage in fatal hypothermia: preliminary results. Am J Forensic Med Pathol. 2019;40(3):242\u20135.","journal-title":"Am J Forensic Med Pathol"},{"issue":"2","key":"772_CR15","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1080\/20961790.2021.1886656","volume":"7","author":"MA Ibrahim","year":"2021","unstructured":"Ibrahim MA, Mohammed SS, Tammam HG, Ibrahim Abdel-Karim R, Farag MM. Histopathological, histochemical and biochemical postmortem changes in induced fatal hypothermia in rats. Forensic Sci Res. 2021;7(2):211\u201327.","journal-title":"Forensic Sci Res"},{"issue":"4","key":"772_CR16","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1097\/JNN.0000000000000142","volume":"47","author":"LK Madden","year":"2015","unstructured":"Madden LK, DeVon HA. A systematic review of the effects of body temperature on outcome after adult traumatic brain injury. J Neurosci Nurs. 2015;47(4):190\u2013203.","journal-title":"J Neurosci Nurs"},{"issue":"11","key":"772_CR17","doi-asserted-by":"publisher","first-page":"863","DOI":"10.2176\/nmc.st.2014-0160","volume":"54","author":"E Suehiro","year":"2014","unstructured":"Suehiro E, Koizumi H, Fujiyama Y, Suzuki M. Recent advances and future directions of hypothermia therapy for traumatic brain injury. Neurol Med Chir (Tokyo). 2014;54(11):863\u20139.","journal-title":"Neurol Med Chir (Tokyo)"},{"issue":"2","key":"772_CR18","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1227\/00006123-199408000-00013","volume":"35","author":"A Kader","year":"1994","unstructured":"Kader A, Frazzini VI, Baker CJ, Solomon RA, Trifiletti RR. Effect of mild hypothermia on nitric oxide synthesis during focal cerebral ischemia. Neurosurgery. 1994;35(2):272\u20137.","journal-title":"Neurosurgery"},{"key":"772_CR19","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/957054","volume":"2013","author":"N Alva","year":"2013","unstructured":"Alva N, Palomeque J, Carbonell T. Oxidative stress and antioxidant activity in hypothermia and rewarming: can RONS modulate the beneficial effects of therapeutic hypothermia? Oxid Med Cell Longev. 2013;2013: 957054.","journal-title":"Oxid Med Cell Longev"},{"key":"772_CR20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2020.111360","volume":"206","author":"X Ren","year":"2020","unstructured":"Ren X, Yu Z, Xu Y, Zhang Y, Mu C, Liu P, et al. Integrated transcriptomic and metabolomic responses in the hepatopancreas of kuruma shrimp (Marsupenaeus japonicus) under cold stress. Ecotoxicol Environ Saf. 2020;206: 111360.","journal-title":"Ecotoxicol Environ Saf"},{"key":"772_CR21","doi-asserted-by":"publisher","first-page":"112177","DOI":"10.1016\/j.biopha.2021.112177","volume":"143","author":"F Yao","year":"2021","unstructured":"Yao F, Wang X, Cao X, Zhang K, Sun J, Li Y, et al. Integration of transcriptomics and metabolomics confirmed hepatoprotective effects of steamed shoot extracts of ginseng (Panax ginseng C.A. Meyer) on toxicity caused by overdosed acetaminophen. Biomed Pharmacother. 2021;143:112177.","journal-title":"Biomed Pharmacother"},{"issue":"1","key":"772_CR22","first-page":"55","volume":"14","author":"L Ji","year":"2025","unstructured":"Ji L, Shi Q, Chen C, Liu X, Zhu J, Hong X, et al. Biochemical, histological, and multi-omics analyses reveal the molecular and metabolic mechanisms of cold stress response in the Chinese soft-shelled turtle (Pelodiscus sinensis). Biology (Basel). 2025;14(1):55.","journal-title":"Biology (Basel)"},{"issue":"1","key":"772_CR23","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1186\/s12864-019-5915-7","volume":"20","author":"X Wen","year":"2019","unstructured":"Wen X, Hu Y, Zhang X, Wei X, Wang T, Yin S. Integrated application of multi-omics provides insights into cold stress responses in pufferfish Takifugu fasciatus. BMC Genomics. 2019;20(1):563.","journal-title":"BMC Genomics"},{"issue":"2","key":"772_CR24","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41419-023-05691-6","volume":"14","author":"K Ye","year":"2023","unstructured":"Ye K, Chen Z, Xu Y. The double-edged functions of necroptosis. Cell Death Dis. 2023;14(2):163.","journal-title":"Cell Death Dis"},{"issue":"2","key":"772_CR25","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nchembio711","volume":"1","author":"A Degterev","year":"2005","unstructured":"Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1(2):112\u20139.","journal-title":"Nat Chem Biol"},{"key":"772_CR26","doi-asserted-by":"publisher","first-page":"24547","DOI":"10.1038\/srep24547","volume":"6","author":"T Liu","year":"2016","unstructured":"Liu T, Zhao DX, Cui H, Chen L, Bao YH, Wang Y, et al. Therapeutic hypothermia attenuates tissue damage and cytokine expression after traumatic brain injury by inhibiting necroptosis in the rat. Sci Rep. 2016;6:24547.","journal-title":"Sci Rep"},{"issue":"6","key":"772_CR27","doi-asserted-by":"publisher","first-page":"3028","DOI":"10.3390\/ijms22063028","volume":"22","author":"J Ren","year":"2021","unstructured":"Ren J, Long Y, Liu R, Song G, Li Q, Cui Z. Characterization of biological pathways regulating acute cold resistance of zebrafish. Int J Mol Sci. 2021;22(6):3028.","journal-title":"Int J Mol Sci"},{"issue":"19","key":"772_CR28","doi-asserted-by":"publisher","first-page":"11442","DOI":"10.3390\/ijms231911442","volume":"23","author":"R Liu","year":"2022","unstructured":"Liu R, Long Y, Liu R, Song G, Li Q, Yan H, Cui Z. Understanding the function and mechanism of zebrafish tmem39b in regulating cold resistance. Int J Mol Sci. 2022;23(19):11442.","journal-title":"Int J Mol Sci"},{"issue":"3","key":"772_CR29","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1016\/j.antiviral.2013.06.008","volume":"99","author":"E Haasbach","year":"2013","unstructured":"Haasbach E, Reiling SJ, Ehrhardt C, Droebner K, R\u00fcckle A, Hrincius ER, et al. The NF-kappaB inhibitor SC75741 protects mice against highly pathogenic avian influenza A virus. Antiviral Res. 2013;99(3):336\u201344.","journal-title":"Antiviral Res"},{"issue":"6","key":"772_CR30","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1111\/fcp.13030","volume":"38","author":"Y Hekmatshoar","year":"2024","unstructured":"Hekmatshoar Y, Karabay AZ, Ozkan T, Koc A, Sunguroglu A. Methylsulfonylmethane induces caspase-dependent apoptosis in acute myeloid leukemia cell lines. Fundam Clin Pharmacol. 2024;38(6):1094\u2013102.","journal-title":"Fundam Clin Pharmacol"},{"key":"772_CR31","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107429","volume":"148","author":"F Doganc","year":"2024","unstructured":"Doganc F, Ozkan T, Farhangzad N, Mavideniz A, Celik I, Sunguroglu A, et al. Synthesis of novel indol-3-acetamido analogues as potent anticancer agents, biological evaluation and molecular modeling studies. Bioorg Chem. 2024;148: 107429.","journal-title":"Bioorg Chem"},{"issue":"4","key":"772_CR32","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","volume":"12","author":"D Kim","year":"2015","unstructured":"Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12(4):357\u201360.","journal-title":"Nat Methods"},{"issue":"3","key":"772_CR33","doi-asserted-by":"publisher","first-page":"R22","DOI":"10.1186\/gb-2011-12-3-r22","volume":"12","author":"A Roberts","year":"2011","unstructured":"Roberts A, Trapnell C, Donaghey J, Rinn JL, Pachter L. Improving RNA-Seq expression estimates by correcting for fragment bias. Genome Biol. 2011;12(3):R22.","journal-title":"Genome Biol"},{"issue":"2","key":"772_CR34","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166\u20139.","journal-title":"Bioinformatics"},{"issue":"12","key":"772_CR35","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.","journal-title":"Genome Biol"},{"issue":"D1","key":"772_CR36","doi-asserted-by":"publisher","first-page":"D330","DOI":"10.1093\/nar\/gky1055","volume":"47","author":"The Gene Ontology Consortium","year":"2019","unstructured":"The Gene Ontology Consortium. The gene ontology resource: 20 years and still going strong. Nucleic Acids Res. 2019;47(D1):D330\u20138.","journal-title":"Nucleic Acids Res"},{"key":"772_CR37","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1093\/nar\/gkm882","volume":"36","author":"M Kanehisa","year":"2008","unstructured":"Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res. 2008;36:480\u20134.","journal-title":"Nucleic Acids Res"},{"issue":"43","key":"772_CR38","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545\u201350.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"772_CR39","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1186\/s12964-023-01359-y","volume":"21","author":"W Xie","year":"2023","unstructured":"Xie W, Peng M, Liu Y, Zhang B, Yi L, Long Y. Simvastatin induces pyroptosis via ROS\/caspase-1\/GSDMD pathway in colon cancer. Cell Commun Signal. 2023;21(1):329.","journal-title":"Cell Commun Signal"},{"issue":"1","key":"772_CR40","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3390\/ijms23010003","volume":"23","author":"ML Tsai","year":"2021","unstructured":"Tsai ML, Tsai YG, Lin YC, Hsu YL, Chen YT, Tsai MK, et al. IL-25 induced ROS-mediated M2 macrophage polarization via AMPK-associated mitophagy. Int J Mol Sci. 2021;23(1):3.","journal-title":"Int J Mol Sci"},{"issue":"Pt B","key":"772_CR41","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.arr.2015.09.002","volume":"24","author":"J Hanus","year":"2015","unstructured":"Hanus J, Anderson C, Wang S. RPE necroptosis in response to oxidative stress and in AMD. Ageing Res Rev. 2015;24(Pt B):286\u201398.","journal-title":"Ageing Res Rev"},{"issue":"6","key":"772_CR42","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1038\/s12276-021-00634-7","volume":"53","author":"J Seo","year":"2021","unstructured":"Seo J, Nam YW, Kim S, Oh DB, Song J. Necroptosis molecular mechanisms: recent findings regarding novel necroptosis regulators. Exp Mol Med. 2021;53(6):1007\u201317.","journal-title":"Exp Mol Med"},{"key":"772_CR43","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113925","volume":"156","author":"M Yang","year":"2022","unstructured":"Yang M, Chen W, He L, Liu D, Zhao L, Wang X. A Glimpse of necroptosis and diseases. Biomed Pharmacother. 2022;156: 113925.","journal-title":"Biomed Pharmacother"},{"issue":"12","key":"772_CR44","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1177\/1535370216644531","volume":"241","author":"NS Chang","year":"2016","unstructured":"Chang NS. Bubbling cell death: a hot air balloon released from the nucleus in the cold. Exp Biol Med (Maywood). 2016;241(12):1306\u201315.","journal-title":"Exp Biol Med (Maywood)"},{"issue":"10","key":"772_CR45","doi-asserted-by":"publisher","first-page":"8007","DOI":"10.18632\/oncotarget.3153","volume":"6","author":"SJ Chen","year":"2015","unstructured":"Chen SJ, Lin PW, Lin HP, Huang SS, Lai FJ, Sheu HM, et al. UV irradiation\/cold shock-mediated apoptosis is switched to bubbling cell death at low temperatures. Oncotarget. 2015;6(10):8007\u201318.","journal-title":"Oncotarget"},{"key":"772_CR46","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2023.101755","volume":"37","author":"W Zhu","year":"2023","unstructured":"Zhu W, Yu Y, Ye Y, Tu X, Zhang Y, Wu T, et al. MiR-196b-5p activates NF-\u03baB signaling in non-small cell lung cancer by directly targeting NFKBIA. Transl Oncol. 2023;37: 101755.","journal-title":"Transl Oncol"},{"issue":"7","key":"772_CR47","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1111\/cmi.12108","volume":"15","author":"C Ehrhardt","year":"2013","unstructured":"Ehrhardt C, R\u00fcckle A, Hrincius ER, Haasbach E, Anhlan D, Ahmann K, et al. The NF-\u03baB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance. Cell Microbiol. 2013;15(7):1198\u2013211.","journal-title":"Cell Microbiol"},{"issue":"5","key":"772_CR48","doi-asserted-by":"publisher","DOI":"10.1016\/j.psj.2021.101085","volume":"100","author":"B Tian","year":"2021","unstructured":"Tian B, Cai D, Wang M, He T, Deng L, Wu L, et al. SC75741 antagonizes vesicular stomatitis virus, duck Tembusu virus, and duck plague virus infection in duck cells through promoting innate immune responses. Poult Sci. 2021;100(5): 101085.","journal-title":"Poult Sci"},{"issue":"12","key":"772_CR49","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.3390\/jpm13121690","volume":"13","author":"G Savioli","year":"2023","unstructured":"Savioli G, Ceresa IF, Bavestrello Piccini G, Gri N, Nardone A, La Russa R, et al. Hypothermia: beyond the narrative review-the point of view of emergency physicians and medico-legal considerations. J Pers Med. 2023;13(12):1690.","journal-title":"J Pers Med"},{"issue":"1","key":"772_CR50","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.jinsphys.2010.10.004","volume":"57","author":"HA Macmillan","year":"2011","unstructured":"Macmillan HA, Sinclair BJ. Mechanisms underlying insect chill-coma. J Insect Physiol. 2011;57(1):12\u201320.","journal-title":"J Insect Physiol"},{"key":"772_CR51","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1146\/annurev.ph.57.030195.000315","volume":"57","author":"JR Hazel","year":"1995","unstructured":"Hazel JR. Thermal adaptation in biological membranes: is homeoviscous adaptation the explanation? Annu Rev Physiol. 1995;57:19\u201342.","journal-title":"Annu Rev Physiol"},{"issue":"Pt 18","key":"772_CR52","doi-asserted-by":"publisher","first-page":"3171","DOI":"10.1242\/jeb.204.18.3171","volume":"204","author":"RG Boutilier","year":"2001","unstructured":"Boutilier RG. Mechanisms of cell survival in hypoxia and hypothermia. J Exp Biol. 2001;204(Pt 18):3171\u201381.","journal-title":"J Exp Biol"},{"key":"772_CR53","doi-asserted-by":"publisher","first-page":"660124","DOI":"10.3389\/fphys.2021.660124","volume":"12","author":"H Ei Marzouki","year":"2021","unstructured":"Ei Marzouki H, Aboussaleh Y, Najimi M, Chigr F, Ahami A. Effect of cold stress on neurobehavioral and physiological parameters in rats. Front Physiol. 2021;12:660124.","journal-title":"Front Physiol"},{"issue":"2","key":"772_CR54","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s12640-015-9525-0","volume":"28","author":"MM Ahmadian-Attari","year":"2015","unstructured":"Ahmadian-Attari MM, Dargahi L, Mosaddegh M, Kamalinejad M, Khallaghi B, Noorbala F, et al. Impairment of rat spatial learning and memory in a new model of cold water-induced chronic hypothermia: implication for Alzheimer\u2019s Disease. Neurotox Res. 2015;28(2):95\u2013107.","journal-title":"Neurotox Res"},{"issue":"2\u20133","key":"772_CR55","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.forsciint.2008.04.023","volume":"179","author":"T Ishikawa","year":"2008","unstructured":"Ishikawa T, Quan L, Li DR, Zhao D, Michiue T, Hamel M, et al. Postmortem biochemistry and immunohistochemistry of adrenocorticotropic hormone with special regard to fatal hypothermia. Forensic Sci Int. 2008;179(2\u20133):147\u201351.","journal-title":"Forensic Sci Int"},{"issue":"Suppl 1","key":"772_CR56","doi-asserted-by":"publisher","first-page":"S228","DOI":"10.1016\/j.legalmed.2009.02.049","volume":"11","author":"T Ishikawa","year":"2009","unstructured":"Ishikawa T, Michiue T, Zhao D, Komatsu A, Azuma Y, Quan L, et al. Evaluation of postmortem serum and cerebrospinal fluid levels of thyroid-stimulating hormone with special regard to fatal hypothermia. Leg Med (Tokyo). 2009;11(Suppl 1):S228\u201330.","journal-title":"Leg Med (Tokyo)"},{"issue":"3","key":"772_CR57","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.legalmed.2004.05.004","volume":"6","author":"T Ishikawa","year":"2004","unstructured":"Ishikawa T, Miyaishi S, Tachibana T, Ishizu H, Zhu BL, Maeda H. Fatal hypothermia related vacuolation of hormone-producing cells in the anterior pituitary. Leg Med (Tokyo). 2004;6(3):157\u201363.","journal-title":"Leg Med (Tokyo)"},{"issue":"1\u20133","key":"772_CR58","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.forsciint.2013.03.003","volume":"229","author":"K Ba\u0144ka","year":"2013","unstructured":"Ba\u0144ka K, Teresi\u0144ski G, Buszewicz G, M\u0105dro R. Glucocorticosteroids as markers of death from hypothermia. Forensic Sci Int. 2013;229(1\u20133):60\u20135.","journal-title":"Forensic Sci Int"},{"key":"772_CR59","doi-asserted-by":"publisher","DOI":"10.1016\/j.tice.2022.101984","volume":"80","author":"SJ Wang","year":"2023","unstructured":"Wang SJ, Liu BR, Zhang F, Li YP, Su XR, Yang CT, et al. Abnormal fatty acid metabolism and ceramide expression may discriminate myocardial infarction from strangulation death: a pilot study. Tissue Cell. 2023;80: 101984.","journal-title":"Tissue Cell"},{"issue":"4","key":"772_CR60","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1111\/j.1365-201X.2005.01464.x","volume":"184","author":"J Lepp\u00e4luoto","year":"2005","unstructured":"Lepp\u00e4luoto J, P\u00e4\u00e4kk\u00f6nen T, Korhonen I, Hassi J. Pituitary and autonomic responses to cold exposures in man. Acta Physiol Scand. 2005;184(4):255\u201364.","journal-title":"Acta Physiol Scand"},{"key":"772_CR61","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.forsciint.2013.10.028","volume":"234","author":"K Ba\u0144ka","year":"2014","unstructured":"Ba\u0144ka K, Teresi\u0144ski G, Buszewicz G. Free fatty acids as markers of death from hypothermia. Forensic Sci Int. 2014;234:79\u201385.","journal-title":"Forensic Sci Int"},{"issue":"3","key":"772_CR62","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.ymgme.2019.12.014","volume":"129","author":"A Anderson","year":"2020","unstructured":"Anderson A, Gropman A, Le Mons C, Stratakis C, Gandjbakhche A. Evaluation of neurocognitive function of prefrontal cortex in ornithine transcarbamylase deficiency. Mol Genet Metab. 2020;129(3):207\u201312.","journal-title":"Mol Genet Metab"},{"key":"772_CR63","doi-asserted-by":"publisher","first-page":"109526","DOI":"10.1016\/j.abb.2023.109526","volume":"736","author":"FF Lopes","year":"2023","unstructured":"Lopes FF, Lamberty Faverzani J, Hammerschmidt T, Aguilar Delgado C, Ferreira de Oliveira J, Wajner M, et al. Evaluation of oxidative damage to biomolecules and inflammation in patients with urea cycle disorders. Arch Biochem Biophys. 2023;736:109526.","journal-title":"Arch Biochem Biophys"},{"key":"772_CR64","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.cca.2017.11.041","volume":"477","author":"B Parmeggiani","year":"2018","unstructured":"Parmeggiani B, Vargas CR. Oxidative stress in urea cycle disorders: findings from clinical and basic research. Clin Chim Acta. 2018;477:121\u20136.","journal-title":"Clin Chim Acta"},{"issue":"7879","key":"772_CR65","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/s41586-021-03955-9","volume":"598","author":"KS Matho","year":"2021","unstructured":"Matho KS, Huilgol D, Galbavy W, He M, Kim G, An X, et al. Genetic dissection of the glutamatergic neuron system in cerebral cortex. Nature. 2021;598(7879):182\u20137.","journal-title":"Nature"},{"key":"772_CR66","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.668002","volume":"12","author":"K Mao","year":"2021","unstructured":"Mao K, Luo P, Geng W, Xu J, Liao Y, Zhong H, et al. An integrative transcriptomic and metabolomic study revealed that melatonin plays a protective role in chronic lung inflammation by reducing necroptosis. Front Immunol. 2021;12: 668002.","journal-title":"Front Immunol"},{"issue":"2","key":"772_CR67","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1111\/cns.13765","volume":"28","author":"H Ding","year":"2022","unstructured":"Ding H, Li Y, Chen S, Wen Y, Zhang S, Luo E, et al. Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis-associated encephalopathy. CNS Neurosci Ther. 2022;28(2):247\u201358.","journal-title":"CNS Neurosci Ther"},{"key":"772_CR68","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.freeradbiomed.2017.04.010","volume":"108","author":"W Sun","year":"2017","unstructured":"Sun W, Wu X, Gao H, Yu J, Zhao W, Lu JJ, et al. Cytosolic calcium mediates RIP1\/RIP3 complex-dependent necroptosis through JNK activation and mitochondrial ROS production in human colon cancer cells. Free Radic Biol Med. 2017;108:433\u201344.","journal-title":"Free Radic Biol Med"},{"key":"772_CR69","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2021.126704","volume":"421","author":"X Chen","year":"2022","unstructured":"Chen X, Bi M, Yang J, Cai J, Zhang H, Zhu Y, et al. Cadmium exposure triggers oxidative stress, necroptosis, Th1\/Th2 imbalance and promotes inflammation through the TNF-\u03b1\/NF-\u03baB pathway in swine small intestine. J Hazard Mater. 2022;421: 126704.","journal-title":"J Hazard Mater"},{"issue":"5","key":"772_CR70","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41422-019-0164-5","volume":"29","author":"D Tang","year":"2019","unstructured":"Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29(5):347\u201364.","journal-title":"Cell Res"},{"issue":"4","key":"772_CR71","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3892\/ijmm.2023.5301","volume":"52","author":"S Chen","year":"2023","unstructured":"Chen S, Guan S, Yan Z, Ouyang F, Li S, Liu L, et al. Role of RIPK3-CaMKII-mPTP signaling pathway-mediated necroptosis in cardiovascular diseases (Review). Int J Mol Med. 2023;52(4):98.","journal-title":"Int J Mol Med"},{"key":"772_CR72","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1089\/ars.2007.1658","volume":"9","author":"MJ Morgan","year":"2007","unstructured":"Morgan MJ, Kim YS, Liu Z. Lipid rafts and oxidative stress-induced cell death. Antioxid Redox Signal. 2007;9:1471\u201383.","journal-title":"Antioxid Redox Signal"},{"key":"772_CR73","doi-asserted-by":"publisher","first-page":"5796","DOI":"10.1038\/onc.2015.35","volume":"34","author":"B Schenk","year":"2015","unstructured":"Schenk B, Fulda S. Reactive oxygen species regulate Smac mimetic\/TNF\u03b1- induced necroptotic signaling and cell death. Oncogene. 2015;34:5796\u2013806.","journal-title":"Oncogene"},{"issue":"4","key":"772_CR74","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1002\/jor.23751","volume":"36","author":"L Zhao","year":"2018","unstructured":"Zhao L, Lin H, Chen S, Chen S, Cui M, Shi D, et al. Hydrogen peroxide induces programmed necrosis in rat nucleus pulposus cells through the RIP1\/RIP3- PARP-AIF pathway. J Orthop Res. 2018;36(4):1269\u201382.","journal-title":"J Orthop Res"},{"key":"772_CR75","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1126\/science.1172308","volume":"325","author":"DW Zhang","year":"2009","unstructured":"Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325:332\u20136.","journal-title":"Science"},{"key":"772_CR76","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/cdd.2010.138","volume":"18","author":"N Vanlangenakker","year":"2011","unstructured":"Vanlangenakker N, Vanden Berghe T, Bogaert P, Laukens B, Zobel K, Deshayes K, et al. cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1\/RIP3-dependent reactive oxygen species production. Cell Death Differ. 2011;18:656\u201365.","journal-title":"Cell Death Differ"},{"issue":"5","key":"772_CR77","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1038\/cr.2016.26","volume":"26","author":"B Xia","year":"2016","unstructured":"Xia B, Fang S, Chen X, Hu H, Chen P, Wang H, et al. MLKL forms cation channels. Cell Res. 2016;26(5):517\u201328.","journal-title":"Cell Res"}],"container-title":["Cellular &amp; Molecular Biology Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s11658-025-00772-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s11658-025-00772-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s11658-025-00772-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T19:03:43Z","timestamp":1757271823000},"score":1,"resource":{"primary":{"URL":"https:\/\/cmbl.biomedcentral.com\/articles\/10.1186\/s11658-025-00772-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,21]]},"references-count":77,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["772"],"URL":"https:\/\/doi.org\/10.1186\/s11658-025-00772-0","relation":{},"ISSN":["1689-1392"],"issn-type":[{"value":"1689-1392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,21]]},"assertion":[{"value":"19 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The Animal Care and Use Committee of Hebei Medical University adheres to the principles and guidelines set forth by the International Council for Laboratory Animal Science (ICLAS), ensuring that our animal research meets international ethical standards. A total of 216 C57BL\/6N mice were approved in the study design on 30 March 2022 by the Animal Care and Ethics Committee of Hebei Medical University (approval number: 20223011).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no potential competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"87"}}