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The venom of Type A animals primarily contains \u03b2-neurotoxin referred to as Mojave Toxin (MTX), which makes bites from this snake particularly feared. We performed a genome-wide transcriptomic analysis of the neurocellular response to Mojave Type A rattlesnake venom using induced pluripotent stem cell-derived neural stem cells to unveil the molecular mechanisms underlying the damage caused by this snake\u2019s envenomation. Our results suggest that snake venom metalloproteases, although having a limited repertoire in Type A venom, facilitate venom spread by digesting the tissue\u2019s extracellular matrix. The MTX, which is composed of heterodimers of basic and acidic phospholipase-A2, co-opts the host arachidonic acid and Ca2+ second messenger mechanisms and triggers multiple signaling cascades, such as the activation of MAPKs and NF-\u03baB-regulated proinflammatory genes; the neurotransmitter overload in excitatory synapses leading to a presynaptic blockade of nerve signals; and the upregulation of unfolded protein response (UPR) due to the depletion of Ca2+ from the endoplasmic reticulum. The upregulated UPR and the oxidative stress caused by reactive oxygen species generated in cytochromeP4501A1-mediated hydroxylation of arachidonic acid contribute to mitochondrial toxicity. The activation of UPR, mitochondrial toxicity, and oxidative stress synergistically contributed to apoptotic and ferroptotic cell death.<\/jats:p>","DOI":"10.3390\/biom15030381","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T06:02:13Z","timestamp":1741240933000},"page":"381","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1969-4431","authenticated-orcid":false,"given":"Satish","family":"Kumar","sequence":"first","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1778-0213","authenticated-orcid":false,"given":"Miriam","family":"Aceves","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Granados","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Guerra","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"Juarez","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Earl","family":"Novilla","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7640-3469","authenticated-orcid":false,"given":"Ana","family":"C. Leandro","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Leandro","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8811-5579","authenticated-orcid":false,"given":"Juan","family":"Peralta","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Williams-Blangero","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA"},{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5222-8873","authenticated-orcid":false,"given":"Elda E.","family":"Sanchez","sequence":"additional","affiliation":[{"name":"National Natural Toxin Research Center (NNTRC), Texas A&M University-Kingsville, Kingsville, TX 78363, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3304-0474","authenticated-orcid":false,"given":"Jacob A.","family":"Galan","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6250-5723","authenticated-orcid":false,"given":"John","family":"Blangero","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne E.","family":"Curran","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ajem.2020.08.083","article-title":"Epidemiology of fatal snakebites in the United States 1989\u20132018","volume":"45","author":"Greene","year":"2021","journal-title":"Am. 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