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METH abuse often occurs in crowded, poorly ventilated environments, and even moderately high ambient temperatures exacerbate METH-related cardiovascular emergencies. However, the underlying mechanisms by which environmental factors drive the progression of cardiac diseases remain poorly understood. This study modeled the real-world scenario in vivo by exposing mice to METH under normothermic condition (NC, 22 \u00b0C) or subthreshold thermal stress (STS, 28 \u00b0C, a mild thermal challenge for mice) conditions, and in vitro by using H9c2 cardiomyocytes exposed to METH at 37 \u00b0C or 39 \u00b0C. STS significantly potentiated METH-induced cardiac dysfunction, mitochondrial ultrastructural damage, and oxidative stress (p &lt; 0.05). Mechanistically, the co-exposure impaired mitochondrial respiratory chain complex I and led to excessive mitochondrial ROS (mtROS) production, activating the pro-apoptotic protein BAX, causing mitochondrial outer membrane (MOM) permeabilization and the cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA-mediated NLRP3 inflammasome activation subsequently executed cardiomyocyte pyroptosis via caspase-1\/Gasdermin D (p &lt; 0.05). Crucially, the mitochondria-targeted antioxidant mitoquinone (MitoQ) substantially attenuated the aggravated cardiotoxicity by scavenging the initial mtROS (p &lt; 0.05), thereby preventing the activation of the downstream BAX\/mtDNA\/NLRP3 axis. These findings provide evidence for a defined signaling basis for this drug-environment interaction and highlight mitochondrial redox modulation as a potential therapeutic strategy for psychostimulant-associated cardiovascular injury.<\/jats:p>","DOI":"10.3390\/ijms27115000","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:45:08Z","timestamp":1780404308000},"page":"5000","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Subthreshold Thermal Stress Aggravates Methamphetamine-Induced Cardiomyocyte Pyroptosis via the Mitochondrial ROS\/BAX\/mtDNA\/NLRP3 Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Mengmeng","family":"Wang","sequence":"first","affiliation":[{"name":"Clinical Medical College, Hebei University, Baoding 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congcong","family":"Hou","sequence":"additional","affiliation":[{"name":"College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglian","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6004-1547","authenticated-orcid":false,"given":"Xintao","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunling","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Key Laboratory of Forensic Medicine, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2232-1000","authenticated-orcid":false,"given":"Jianhong","family":"Shi","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hebei University, Baoding 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Ni","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hebei University, Baoding 071000, China"},{"name":"College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Key Laboratory of Forensic Medicine, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s40199-017-0170-4","article-title":"Histopathological study of cardiac lesions in methamphetamine poisoning-related deaths","volume":"25","author":"Akhgari","year":"2017","journal-title":"Daru"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.drugalcdep.2017.07.001","article-title":"Prevalence and nature of cardiovascular disease in methamphetamine-related death: A national study","volume":"179","author":"Darke","year":"2017","journal-title":"Drug Alcohol. 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