Cardiovascular Toxicology最新文献

{"title":"The Vascular Genome as a Therapeutic Target: A Systematic Review of CRISPR-based Gene Editing In Vascular Disease.","authors":"Abiya Ahad, Darshan Hullon, Tanya Singh, Sultan Mujib Dabiry, Lalenthika Sakthivel, Jeel Padaria, Akshay Singh Rekhraj, Aditya Bhattacharjee","doi":"10.1007/s12012-026-10170-3","DOIUrl":"10.1007/s12012-026-10170-3","url":null,"abstract":"<p><p>Despite advances in therapy, arterial, venous, and pulmonary vascular diseases remain leading causes of morbidity and mortality. Persistent endothelial dysfunction, inflammation, oxidative stress, and maladaptive vascular remodeling continue to drive disease progression and residual risk. CRISPR/Cas9 technology offers a unique opportunity to modify the molecular pathways underlying vascular pathophysiology directly. The PRISMA 2020 guidelines guided the systematic review. The databases PubMed/MEDLINE, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and Google Scholar were searched from their inception until September 2025 for experimental and/or clinical studies evaluating the application of CRISPR/Cas9 on vascular disease. Included were in vitro studies, animal model studies, and early-phase human studies aimed at targeting the endothelial cell regulatory pathways, inflammatory pathways, metabolic remodeling processes, and hereditary causes of vasculopathy. Seventeen studies met the inclusion criteria. CRISPR technologies targeting PCSK9, NOS3, HIF1A, NLRP3, METTL4, BMPR2, and ACTA2 were identified to enhance repair mechanisms in endothelial cells, regulate inflammation, modulate lipid metabolism, and remodel the vascular system. The human studies demonstrated sustained gene silencing effects following a single dose of CRISPR-induced in vivo editing. The use of CRISPR technology to edit cell genomes offers potential to alter disease progression in vascular medicine, with a growing body of translational evidence supporting the feasibility and durability of the approach.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salidroside Alleviates Mobocertinib-Induced Cardiotoxicity by Improving Cardiac Electrophysiology.","authors":"Chi Yan, Xiaohong Liu, Xiaoyan Zhang, Pei Wei, Xuefang Li, Dongxu Li, Guhao Zhang, Meng Li, Xiayan Zang, Guangjian Lu, Fei Lin","doi":"10.1007/s12012-026-10169-w","DOIUrl":"10.1007/s12012-026-10169-w","url":null,"abstract":"<p><p>Mobocertinib, a tyrosine kinase inhibitor approved for EGFR exon 20 insertion-mutated non-small cell lung cancer, induces cardiotoxicity manifesting as QT prolongation. Salidroside, a bioactive compound from Rhodiola rosea, exhibits cardioprotective properties. We investigated electrophysiological mechanisms underlying mobocertinib cardiotoxicity and salidroside's protective efficacy using Langendorff-perfused rat hearts and neonatal rat cardiomyocytes (NRCMs). Hearts were treated with escalating mobocertinib concentrations (214, 428, 856 nM) with or without salidroside (20 μM) pretreatment; cardiac parameters including heart rate, PR, JT, QTc intervals and conduction were mapped via high-resolution multichannel electrophysiology. NRCMs underwent chronic mobocertinib exposure with/without salidroside, followed by transcriptomic sequencing, qRT-PCR, and western blot validation. Mobocertinib concentration-dependently prolonged PR, JT, QTc intervals, increased conduction time/heterogeneity, reduced heart rate/velocity, and JT/QTc prolongation persisted after washout. Salidroside pretreatment markedly attenuated these abnormalities. In NRCMs, mobocertinib prolonged field potential duration and impaired conduction; salidroside normalized parameters. Transcriptomic analysis identified enrichment in calcium signaling, aldosterone synthesis, cGMP-PKG, and adrenergic pathways. Notably, Atp2b2 was upregulated in mobocertinib group but downregulated in salidroside combination group, whereas Agtr1b showed opposite pattern. Thus, salidroside mitigates mobocertinib-induced electrophysiological toxicity by modulating Atp2b2/Agtr1b-related signaling networks, providing a novel cardioprotective strategy against mobocertinib-associated cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13452873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-Metal Regulation of Cardiac Remodeling: Targeting the LOXL2-Ferroptosis Axis in Metal-Induced Cardiac Dysfunction.","authors":"Saif Siddiqui, Siddhi Bagwe Parab, Lokesh Kumar Bhatt","doi":"10.1007/s12012-026-10167-y","DOIUrl":"10.1007/s12012-026-10167-y","url":null,"abstract":"<p><p>Cardiac remodeling is driven by progressive extracellular matrix stiffening and cardiomyocyte loss. Cardiomyocyte death arising from the progression of fibrosis and ferroptosis, which are regulated by interconnected pathogenic pathways such as lysyl oxidase-like (LOXL), Yes-associated protein (YAP) transcriptional coactivator with PDZ-binding motif (TAZ), and transforming growth factor-beta, leads to cardiac remodeling. However, existing treatments are insufficient to restore heart health. There is mounting evidence that maintaining a healthy balance of metals, particularly copper and iron, can protect the heart from metal-induced cell death, cardiac structural remodeling, and extracellular matrix stiffening. This review examines a therapeutic targeting strategy that emphasises the significance of the Cu-LOXL2-Fe-ferroptosis circuit, a mechanometabolic loop that reinforces the extracellular matrix and oxidative cell death. In this dual-chelation approach, copper modulation inhibits LOXL2-driven extracellular matrix stiffening and profibrotic signaling, while iron chelation suppresses iron-dependent lipid peroxidation and ferroptotic cardiomyocyte death. This combined approach provides a more effective treatment window, interrupting the vicious cycle of tissue damage and cardiomyocyte death. There is preliminary evidence that metal chelators may be able to mitigate ferroptosis and fibrosis, which could lead to possible outcomes.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM9-Mediated Degradation of SMAD4 Promotes Pyroptosis and Disruption of the Endothelial Barrier in Aortic Dissection Disease.","authors":"Hong-Qin Bi, Tan Yang, Sheng-Lin Ling, Feng-Xu Yu","doi":"10.1007/s12012-026-10160-5","DOIUrl":"10.1007/s12012-026-10160-5","url":null,"abstract":"<p><p>Aortic dissection (AD) is a life-threatening cardiovascular disease with exceedingly high mortality, particularly during the acute phase. Ubiquitination modification is implicated in the pathogenesis of cardiovascular diseases through diverse biological processes. However, the role of TRIM9, an E3 ubiquitin ligase, in AD remains unexplored. In this study, the expression profiles of TRIM9 and SMAD4 were analyzed using clinical samples, as well as Angiotensin II (Ang II)-induced mouse and human aortic endothelial cell (HAEC) models. Endothelial barrier function in AD was assessed through CCK-8 assays, vascular permeability measurements, immunofluorescence staining, hematoxylin-eosin and Verhoeff's van Gieson staining, and Western blot analysis. The underlying molecular mechanisms were elucidated using quantitative real-time PCR, immunoprecipitation (IP), co-immunoprecipitation (Co-IP), and enzyme-linked immunosorbent assay (ELISA). TRIM9 was markedly overexpressed, whereas SMAD4 was significantly downregulated in AD. Knockdown of TRIM9 attenuated endothelial permeability, preserved the endothelial barrier integrity, and inhibited pyroptosis both in vivo and in vitro. Mechanistically, TRIM9 promoted the ubiquitination and subsequent proteasomal degradation of SMAD4, thereby exacerbating AD progression. Collectively, these findings demonstrate that elevated TRIM9 expression aggravates AD progression through SMAD4 destabilization, offering novel therapeutic insights for AD management.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ApoE-Null Golden Hamster: A Novel Model of Atherosclerosis.","authors":"Guangming Fang, Shiyue Zheng, Jinxin Miao, Yi Zeng, Ying Peng, Yafei Zhai, Haoran Guo, Jianyao Wang, Yiming Dong, Xiaoxu Tian, Mengduan Liu, Yangyang Liu, Xiaowei Li, Mengyu Wang, Xiaoyan Zhao, Jie Du, Yaohe Wang, Jianzeng Dong","doi":"10.1007/s12012-026-10164-1","DOIUrl":"10.1007/s12012-026-10164-1","url":null,"abstract":"<p><p>Atherosclerosis is a chronic, progressive arterial disease characterized by the deposition of lipids on the inner arterial walls, leading to plaque formation and serious cardiovascular events. Traditional mouse models of atherosclerosis require prolonged dietary induction to exhibit arterial lesions due to significant differences in lipid metabolism compared to humans. In contrast, Golden hamsters share a lipid metabolic profile more closely aligned with humans. In this study, we utilized CRISPR/Cas9 to generate ApoE knockout (ApoE^-/-) hamsters using, which spontaneously developed atherosclerotic lesions in the arterial wall after 8 weeks on a standard chow diet. When fed on a high-cholesterol/high-fat diet, they exhibited even more severe aortic atherosclerosis, fatty liver, and liver fibrosis. Our findings demonstrated that the ApoE^-/- hamster model is highly valuable tool for translational research, offering significant potential for studying hyperlipidemia and atherosclerosis in a context more relevant to human physiology.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lapatinib Induces Ferroptosis in Cardiomyocytes by Regulating ATF4/GPX4.","authors":"Yue Sun, Keyi Jiang, Dan Wang, Chunlei Li, Yuqing You, Long Chen, Wei Chang, Liwei Zhang, Hongqi Feng, Dandan Li, Yilan Li","doi":"10.1007/s12012-026-10166-z","DOIUrl":"10.1007/s12012-026-10166-z","url":null,"abstract":"<p><p>The TKI-targeted agent lapatinib has been applied in clinical oncology for the management of multiple malignancies. Nonetheless, its therapeutic benefit is restricted by cardiotoxic effects that endanger patient survival, and the underlying molecular basis remains unclear. The GSE146096 dataset containing transcriptomic profiles of lapatinib-exposed human cardiomyocytes was analyzed to identify ferroptosis-related differentially expressed genes (DEGs). Protein expression of selected targets was subsequently confirmed by Western Blot. Reactive oxygen species (ROS) accumulation, Fe²⁺ levels, and mitochondrial membrane potential in AC16 cells exposed to lapatinib were examined using confocal microscopy. A microplate reader was employed to quantify alterations in malondialdehyde (MDA) and glutathione (GSH) levels in cardiomyocytes. Eight ferroptosis-associated genes were identified in lapatinib-treated cardiomyocytes, including the canonical regulator GPX4. siRNA interference and Western Blot analyses demonstrated marked induction of ATF4 expression and significant suppression of GPX4 expression following lapatinib exposure in AC16 cells. CCK-8 assays indicated dose-dependent cytotoxicity. Confocal microscopy and transmission electron microscopy (TEM) revealed altered mitochondrial morphology accompanied by a reduction in mitochondrial membrane potential. Intracellular MDA levels increased substantially, whereas GSH levels declined, indicating lipid peroxidation and subsequent ferroptosis. Treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) or silencing of ATF4 expression effectively attenuated lapatinib-induced cytotoxicity. Lapatinib enhances ATF4 expression in cardiomyocytes, suppresses GPX4, triggers lipid peroxidation, induces ferroptosis, and thereby contributes to cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methyltransferase METTL1 Upregulates USF2 in a m7G-Dependent Manner to Accelerate Septic Cardiomyopathy by Inactivating PINK1/Parkin-Mediated Mitophagy.","authors":"Wei Dong, Jin Chen, Zhiping Xiong, Ruichun Liao, Junfei Weng, Zhichao Wang, Xiaoping Peng","doi":"10.1007/s12012-026-10144-5","DOIUrl":"10.1007/s12012-026-10144-5","url":null,"abstract":"<p><p>Septic cardiomyopathy (SCM) is a severe complication of sepsis, characterized by high mortality. The activation of mitophagy in cardiomyocytes is crucial for alleviating SCM. The N7-methylguanosine (m7G) modification mediated by methyltransferase 1 (METTL1) is known to negatively regulate mitophagy. This study investigated the mechanism of METTL1 in the mitophagy of cardiomyocytes in SCM. Human cardiomyocytes (HCMs) were stimulated with lipopolysaccharide (LPS) to establish the SCM model. C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to create a septic model. Mitophagy was assessed utilizing the mt-Keima assay, while mitochondrial membrane potential was measured with the JC-1 assay. MitoSOX Red assay was employed to evaluate levels of mitochondrial reactive oxygen species (ROS). The interaction between METTL1 and upstream transcription factor 2 (USF2), as well as between USF2 and PTEN-induced putative kinase protein 1 (PINK1), was confirmed through RNA immunoprecipitation (RIP) and RNA pull-down or dual luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays. The silenced METTL1 mitigated LPS-triggered myocardial damage in vitro. The inhibition of mitophagy nullified the protective effects conferred by METTL1 silencing in LPS-induced HCMs. Consistently, METTL1 silencing ameliorated myocardial injury induced by sepsis in a mouse model. METTL1 enhanced the expression of USF2 in an m7G-dependent manner. USF2, in turn, inactivated the PINK1/Parkin signaling pathway by repressing PINK1 transcription. The repression of USF2 negated the protective effects of METTL1 silencing on myocardial damage and mitophagy. METTL1 aggravated myocardial injury by inhibiting PINK1/Parkin-mediated mitophagy through the upregulation of USF2 in a m7G-dependent manner in SCM models, thereby identifying METTL1 as a potential therapeutic target for SCM.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Micro- and Nanoplastics in Cardiovascular Toxicology: Human Tissue Detection, Clinical Phenotypes, and Adverse Outcome Signals.","authors":"Guangzhen Lu, Xiaoting Wang, Hong Zhuang, Xinye Wang, Gang Zhao","doi":"10.1007/s12012-026-10163-2","DOIUrl":"10.1007/s12012-026-10163-2","url":null,"abstract":"<p><p>Micro- and nanoplastics (MNPs) have emerged from a diffuse environmental concern to a plausible cardiovascular exposure with potential clinical relevance. The current evidence base is heterogeneous: human observational and tissue-detection studies have identified MNPs in blood, thrombi, atherosclerotic plaques, arterial tissue, and cardiac surgical specimens, whereas cell, organoid, and animal studies provide mechanistic plausibility for vascular inflammation, thrombosis, myocardial injury, remodeling, and electrophysiological disturbance. Key clinical signals now include polyethylene detection in 58.4% of carotid plaques and a reported 4.53-fold higher risk of myocardial infarction, stroke, or all-cause death among patients with MNP-positive plaques in the landmark carotid plaque cohort. Accordingly, the central question is no longer only whether MNPs can induce oxidative stress or inflammation in isolated systems, but whether they may contribute to clinically recognizable cardiovascular phenotypes and adverse outcomes. In this review, we reframe the field from a mechanism-dominant narrative toward a clinically oriented synthesis integrating human specimen evidence, disease phenotypes, evidence calibration, analytical limitations, and translational implications. We summarize current human evidence for MNPs presence in circulation and diseased vascular tissues, examine phenotype-specific evidence for atherosclerosis, thrombosis and coagulation disturbance, myocardial injury and fibrotic remodeling, contractile dysfunction, electrophysiological abnormalities, and developmental cardiovascular toxicity, and distinguish these clinical signals from preclinical mechanistic support. Across these phenotypes, the most reproducible mechanisms involve endothelial injury, immunoinflammatory activation, oxidative stress, mitochondrial dysfunction, and prothrombotic signaling. Overall, current evidence supports biological plausibility and clinically relevant associations rather than definitive causality, but the convergence of human tissue detection, phenotype-oriented experiments, and emerging clinical associations justifies considering MNPs as emerging cardiovascular risk modifiers.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tnxb Alleviates Myocardial Ischemia-Reperfusion Injury Through Facilitating Akt-Dependent Endothelial Cell Survival and Angiogenesis in Mice.","authors":"Haohao Hao, Xiaolin Zi, Yunhao Jiang, Jiawen Li","doi":"10.1007/s12012-026-10158-z","DOIUrl":"10.1007/s12012-026-10158-z","url":null,"abstract":"<p><p>Tenascin-X (Tnxb) is a large extracellular matrix protein that has been associated with atherosclerosis. The objective of this study was to investigate the effect of Tnxb and its contribution to recovery after myocardial ischemia/reperfusion (I/R) injury. Tnxb expression was reduced in ECs of mice with ligation of the left anterior descending. Conditional Tnxb overexpression using adeno-associated viruses promoted Akt phosphorylation and mitigated myocardial injury and cardiac dysfunction in mice with myocardial I/R. Furthermore, overexpression of Tnxb alleviated apoptosis and enhanced angiogenesis in vivo and in vitro. Krueppel-like factor 4 (Klf4) recruited SWItch/sucrose nonfermentable (SWI/SNF) to the distal enhancer of Tnxb to transcriptionally activate Tnxb, thereby promoting Akt phosphorylation. The mitigating effect of Klf4 overexpression on I/R-induced endothelial apoptosis and angiogenic dysfunction was dependent on Tnxb activation, since Tnxb knockdown reversed the effects of Klf4 overexpression on myocardial I/R injury. In summary, we show that Klf4 recruits SWI/SNF to the distal enhancer of Tnxb to transcriptionally activate Tnxb, which promotes Akt phosphorylation and alleviates myocardial I/R-induced endothelial apoptosis and angiogenic dysfunction. Lastly, Tnxb was identified as a potential therapeutic target in EC injuries induced by myocardial I/R.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT5 Attenuates Doxorubicin-Induced Acute Cardiac Injury by Modulating PHB2 Succinylation and the Mitophagic Response.","authors":"Aihui Zeng, Haiqiong Liu, Xudong Song, Jing Yan, Yan Zhou, Datong Sun, Aihua Chen","doi":"10.1007/s12012-026-10165-0","DOIUrl":"10.1007/s12012-026-10165-0","url":null,"abstract":"<p><p>Doxorubicin (DOX)-induced cardiac injury remains a major limitation of chemotherapy and is closely linked to mitochondrial dysfunction, oxidative stress, and dysregulated mitophagy. Sirtuin 5 (SIRT5), a mitochondrial deacylation-related protein, has been implicated in mitochondrial homeostasis; however, its role in DOX-induced acute cardiaotoxicity is not fully understood. Here, we investigated whether SIRT5 mitigates acute DOX-induced cardiac injury by regulating prohibitin 2 (PHB2) succinylation and mitochondrial quality control. An acute DOX-induced cardiac-damaged mouse model was established (15 mg/kg for one single dose, i.p.) in male C57BL/6 mice, serum lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and cardiac creatine kinase isoenzyme MB (CK-MB) were elevated, accompanied by reduced cardiac SIRT5 expression. In primary cardiomyocytes, DOX (4 µM, 24 h) downregulated SIRT5 and induced excessive ROS production and apoptosis together with altered mitophagy-related signaling. SIRT5 overexpression attenuated DOX-triggered ROS accumulation and apoptosis and reversed these mitophagy-associated alterations. Mechanistically, PHB2 succinylation was increased upon DOX exposure, whereas SIRT5 overexpression reduced PHB2 succinylation detected by PHB2 immunoprecipitation followed by pan-succinyl-lysine immunoblotting. In addition, SIRT5 showed colocalization and interaction with PHB2. Collectively, our findings suggest that SIRT5 attenuates acute DOX-induced cardiotoxicity, potentially through modulating PHB2 succinylation and the mitophagic response, highlighting the SIRT5-PHB2 axis as a candidate target for alleviating early-onset of DOX-induced cardiac injury.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}