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Studies indicate that the mitochondrial calcium uniporter (MCU) plays a pivotal role in neurotoxic damage induced by psychoactive substances. As the primary channel for mitochondrial Ca2+ uptake, MCU dysfunction can lead to Ca2+ overload, oxidative stress, and apoptosis, representing a crucial mechanism underlying neurotoxic damage. Psychoactive substances such as 3,4-Methylenedioxymethamphetamine (MDMA), cocaine, and morphine influence MCU function through multiple pathways, resulting in excessive Ca2+ accumulation and mitochondrial dysfunction, ultimately leading to neuronal injury. Although MCU inhibitors have demonstrated potential in alleviating Ca2+ overload and improving neural function in preliminary studies, their selectivity and long-term safety require further evaluation. Future research should explore the precise regulatory mechanisms of MCU in neurotoxic damage induced by psychoactive substances and develop more effective targeted therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms26104732","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T06:59:16Z","timestamp":1747292356000},"page":"4732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mitochondrial Calcium Uniporter (MCU)-Mediated Calcium Overload in Psychoactive Drug Neurotoxicity: From Pathogenesis to Therapeutic Targets"],"prefix":"10.3390","volume":"26","author":[{"given":"Xinyan","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Forensic Medicine, Hainan Provincial Tropical Forensic Engineering Research Center, Hainan Medical University, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Forensic Medicine, Hainan Provincial Tropical Forensic Engineering Research Center, Hainan Medical University, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaolin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Forensic Medicine, Hainan Provincial Tropical Forensic Engineering Research Center, Hainan Medical University, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyun","family":"Nie","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Forensic Medicine, Hainan Provincial Tropical Forensic Engineering Research Center, Hainan Medical University, Haikou 571199, China"},{"name":"Department of Pathology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Forensic Medicine, Hainan Provincial Tropical Forensic Engineering Research Center, Hainan Medical University, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/nature10230","article-title":"A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter","volume":"476","author":"Raffaello","year":"2011","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.freeradbiomed.2020.04.002","article-title":"The mechanism of CaMK2\u03b1-MCU-mitochondrial oxidative stress in bupivacaine-induced neurotoxicity","volume":"152","author":"Liu","year":"2020","journal-title":"Free Radic. 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