Article(id=1308817728916517109, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0746, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1751212800000, receivedDateStr=2025-06-30, revisedDate=1762617600000, revisedDateStr=2025-11-09, acceptedDate=null, acceptedDateStr=null, onlineDate=1789976063230, onlineDateStr=2026-09-21, pubDate=1770825600000, pubDateStr=2026-02-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789976063230, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789976063230, creator=13701087609, updateTime=1789976063230, updator=13701087609, issue=Issue{id=1308817633789698171, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='2', pageStart='321', pageEnd='676', issueExtLink='null', onlineDate='null', pubDate='1770825600000', pubDateStr='2026-02-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789976040551, creator='13701087609', updateTime=1789984264575, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308852127921963901, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308852127921963902, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=486, endPage=493, ext={EN=ArticleExt(id=1308817729143009526, articleId=1308817728916517109, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Application of hiPSC-CMs model to compare the reversal effects and mechanisms of different drugs on thioridazine-induced acLQTS, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Drug targeting of the human ether-à-go-go-related gene (hERG)-encoded rapid delayed rectifier potassium channel induces acquired long QT syndrome (acLQTS), predisposing individuals to life-threatening arrhythmias. Previous studies demonstrate that the antipsychotic agent thioridazine (THIO) triggers acLQTS. Our findings aimed to elucidate the underlying mechanisms of the therapeutic effects against drug-induced cardiotoxicity. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) integrated with multi-electrode arrays (MEA) and optical mapping technology, we evaluated and compared the efficacy of tanshinone IIA (TANIIA), propranolol (Prop) and resveratrol (Res) in reversing THIO-induced prolongation of action potential duration (APD) and field potential duration (all animal experiments were conducted in accordance with the Animal Care Guidelines of Harbin Medical University and were approved by the Ethics Committee of Harbin Medical University, the approval number is IRB3020622). The results showed that TANIIA significantly reversed the THIO-induced prolongation of APD₉₀, APD₅₀, and field potential, whereas neither Prop nor Res counteracted this effect. Building on these results, we further explored the mechanistic basis and molecular targets underlying TANIIA's reversal effects. Western blot and whole-cell patch-clamp demonstrated that TANIIA restored hERG protein expression downregulated by THIO and rescued its channel trafficking defects and rescued channel trafficking defects. Mechanistically, TANIIA attenuated THIO-induced aberrant interactions between hERG and the calnexin, thereby rectifying impaired channel folding and trafficking. Concurrently, TANIIA substantially reduced THIO-induced L-type calcium current. In conclusion, TANIIA ameliorates THIO-induced acLQTS by up regulating hERG current expression and down regulating L-type calcium current. These findings highlight its therapeutic potential of drug-induced acLQTS for clinical.

, authors=Jia-xin LI¹, Yan LIU¹, Xiao-xu LI¹, Hai-ying HONG¹, Yu-yan ZHOU¹, Ying SONG¹, Bao-xin LI^{1, *}, Pan FAN^{2, *}, authorsList=Jia-xin LI, Yan LIU, Xiao-xu LI, Hai-ying HONG, Yu-yan ZHOU, Ying SONG, Bao-xin LI, Pan FAN, authorCompany=null, correspAuthors=Bao-xin LI, Pan FAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308817732045467907, articleId=1308817728916517109, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=应用hiPSC-CMs细胞模型比较不同药物对硫利达嗪诱发的acLQTS的逆转作用及机制, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

药物靶向心脏人类ether-à-go-go相关基因(human ether-à-go-go-related gene, hERG) 编码的快速延迟整流钾通道易诱发获得性长QT综合征(acquired long QT syndrome, acLQTS), 使患者发生危及生命的心律失常。抗精神失常药硫利达嗪(thioridazine, THIO) 在临床应用时产生诱发acLQTS的心脏毒性, 如何逆转并探索可能的机制即为本研究的目的。本研究应用人诱导多能干细胞衍生的心肌细胞(human induced pluripotent stem cell derived cardiomyocytes, hiPSC-CMs) 模型, 结合微电极阵列(multi-electrode array, MEA)、高分辨荧光标测技术评价比较了丹参酮ⅡA (tanshinone IIA, TANIIA)、普萘洛尔(propranolol, Prop)、白藜芦醇(resveratrol, Res) 对硫利达嗪引起的动作电位时程(action potential duration, APD)、场电位延长的逆转作用(所有动物实验均按照哈尔滨医科大学动物操作准则进行并得到哈尔滨医科大学伦理委员会的批准, 伦理号-IRB3020622)。结果显示, 丹参酮能够明显逆转硫利达嗪延长的APD₉₀、APD₅₀及场电位, 而普萘洛尔和白藜芦醇两药没有逆转硫利达嗪导致APD及场电位的延长作用。基于以上结果, 本研究进一步探索丹参酮ⅡA发挥逆转作用的机制及靶点。Western blot及全细胞膜片钳检测结果证实, 丹参酮ⅡA对硫利达嗪抑制的hERG蛋白具有明显的拯救作用, 其机制是丹参酮ⅡA通过减弱硫利达嗪造成的hERG蛋白与钙连蛋白(calnexin) 的相互作用, 拯救了硫利达嗪诱发的hERG通道蛋白折叠转运障碍, 同时hERG电流也增加; 此外丹参酮ⅡA明显减少了硫利达嗪所激活的钙电流。综上, 丹参酮ⅡA可以通过上调hERG蛋白、hERG电流及下调钙电流, 最终逆转硫利达嗪诱发的acLQTS, 有望成为临床上治疗acLQTS的有效药物。

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A: APD₅₀ and APD₉₀ representative maps; B: Statistical analysis of APD₅₀ and APD₉₀ of optical mapping. n = 5, $ \overline{x} $ ± SEM. ^*P < 0.05 vs Ctrl; ^#P < 0.05 vs THIO. THIO: Thioridazine; APD: Action potential duration; Prop: Propranolol; TANIIA: Tanshinone IIA; Res: Resveratrol, figureFileSmall=jzON0lo4oRTuLm5jhlooPg==, figureFileBig=Bq6VyIRH9kC/MjPJPoZp+A==, tableContent=null), ArticleFig(id=1308817891563237860, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=E2bI46uLcX5PEVPwvcQzyw==, figureFileBig=z3czag27L9nPHSFEgQmUqA==, tableContent=null), ArticleFig(id=1308817891626152421, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.2, caption=Effects of THIO and reversal drugs on the field potential of hiPSC-CMs. A-F: Representative field potentials of hiPSC-CMs under the following respective drug administration conditions: Ctrl group (A), 3 μmol·L^-1 THIO group (B), 3 μmol·L^-1 THIO + 10 μmol·L^-1 TANIIA group (C), 3 μmol·L^-1 THIO + 10 μmol·L^-1 Prop group (D), and 3 μmol·L^-1 THIO + 10 μmol·L^-1 Res group (E). n = 3, $ \overline{x} $ ± SEM. ^*P < 0.05 vs Ctrl; ^#P < 0.05 vs THIO. hiPSC-CMs: Human induced pluripotent stem cell-derived cardiomyocytes; FPDc: Field potential duration correction, figureFileSmall=E2bI46uLcX5PEVPwvcQzyw==, figureFileBig=z3czag27L9nPHSFEgQmUqA==, tableContent=null), ArticleFig(id=1308817893316456934, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=9oztjoVjDdh5KKYy4YArFQ==, figureFileBig=1L+0w9SC29Z+BHbdX64w1g==, tableContent=null), ArticleFig(id=1308817893391954407, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.3, caption=Rescue effect of TANIIA on THIO-inhibited hERG protein. Western blot results (A) and statistics (B) for hERG expression (incubation for 24 h). THIO significantly reduced 155 kDa of the hERG channel. TANIIA rescues hERG protein inhibited by THIO. n = 5, $ \overline{x} $ ± SEM. ^*P < 0.05 vs Ctrl; ^#P < 0.05 vs THIO, figureFileSmall=9oztjoVjDdh5KKYy4YArFQ==, figureFileBig=1L+0w9SC29Z+BHbdX64w1g==, tableContent=null), ArticleFig(id=1308817893480034792, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=g/HRNehmdmBWQ3exdhOVDg==, figureFileBig=hqBx1xVUvm+XXZyuyZ9XgA==, tableContent=null), ArticleFig(id=1308817893542949353, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.4, caption=Rescue effect of TANIIA on THIO-inhibited hERG channel currents. A: Protocol and examples on the hERG current under Ctrl, THIO-treated and drug-treated conditions; B: I-V curve of the hERG current. THIO reduced the hERG current. TANIIA rescues THIO-inhibited hERG currents. n =11, $ \overline{x} $ ± SEM. ^*P < 0.05 vs Ctrl; ^#P < 0.05 vs THIO, figureFileSmall=g/HRNehmdmBWQ3exdhOVDg==, figureFileBig=hqBx1xVUvm+XXZyuyZ9XgA==, tableContent=null), ArticleFig(id=1308817893626835434, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=X4+WNQ/PBg9GZz2pqiedqg==, figureFileBig=4QPDb7vmaUOlpkICAN2yhw==, tableContent=null), ArticleFig(id=1308817893706527211, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.5, caption=The effect of co-incubation of TANIIA and THIO on the interaction between hERG and chaperones. A, C, E: Representative image of Western blot after immunoprecipitation; B: Statistical result of interaction between hERG and Hsp70; D, F: Statistical result of interaction between hERG and calnexin. n =3, $ \overline{x} $ ± SEM. ^*P < 0.05 vs Ctrl; ^#P < 0.05 vs THIO, figureFileSmall=X4+WNQ/PBg9GZz2pqiedqg==, figureFileBig=4QPDb7vmaUOlpkICAN2yhw==, tableContent=null), ArticleFig(id=1308817893782024684, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=EN, label=null, caption=null, figureFileSmall=Jc5wHsUKEx5PSVIOy3DOZg==, figureFileBig=59JBB+qxyVGRLjVGeWVvBw==, tableContent=null), ArticleFig(id=1308817893870105069, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817728916517109, language=CN, label=Fig.6, caption=Effect of drugs on THIO-enhanced I_{Ca, L} currents. 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