Cardiovascular Toxicology最新文献

{"title":"Role of L-Arginine and Tetrahydrobiopterin in Attenuation of Vascular Ang1-8 Reactivity via Endothelial PI3K/AKT/eNOS Signaling Pathways in HgCl2-Induced Vascular Dysfunction. An Ex-Vivo Study.","authors":"Zana Hassan Ibrahim, Ridha Hassan Hussein, Ismail Mustafa Maulood","doi":"10.1007/s12012-026-10143-6","DOIUrl":"10.1007/s12012-026-10143-6","url":null,"abstract":"<p><p>Vascular endothelial dysfunction because of environmental mercuric chloride (HgCl₂) exposure is well known to induce cardiovascular diseases and heightened vascular responsiveness to angiotensin II (Ang 1-8). The PI3K/AKT/eNOS signaling pathway is essential for preserving endothelial NO bioavailability. Nevertheless, the reasons underlying this dysfunction during oxidative stress are inadequately elucidated. This study explored the roles of L-arginine (LA) and tetrahydrobiopterin (BH₄) both alone and in combination on Ang1-8-induced vascular responses via the endothelial PI3K/AKT/eNOS pathway against HgCl₂ -induced vascular dysfunction in rat aortic rings. In comparison to control (CT) rings; HgCl₂ markedly modified Ang1-8 vascular reactivity, consistent with eNOS uncoupling and oxidative dysregulation. Inhibition of PI3K or AKT further amplified these effects, thereby confirming the vasoprotective role of the PI3K/AKT/eNOS system. The co-administration of LA and BH₄ significantly restored both Emax and pD₂ values in the presence of HgCl₂ and inhibitors, indicating improved NO bioavailability and re-coupled eNOS activity. Treatments of LA and BH4 together sustained endothelial PI3K/AKT/eNOS signaling and alleviate HgCl₂-induced vascular hyperreactivity to Ang1-8 through restoration of NO/cGMP-mediated relaxation, reduces oxidative damage, and enhances antioxidant capacity. These results highlight a potential therapy strategy focused on resolving substrate-cofactor coupling and reinstating endothelial signaling to mitigate heavy metal-induced vascular dysfunction.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249346","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":"A Bibliometric Review and Knowledge Mapping of Microplastics and Nanoplastics in Cardiovascular Research.","authors":"Huihui Chen, Liyi Xu, Yuanqi Wang, Hanlin Zhuo, Hua Zhou, Xuhui Chen, Chongbo Fang","doi":"10.1007/s12012-026-10136-5","DOIUrl":"10.1007/s12012-026-10136-5","url":null,"abstract":"<p><p>Microplastics and nanoplastics (MNPs) have been detected in human blood and cardiovascular tissues, raising concerns about their potential role in cardiovascular disease (CVD). However, the overall research landscape-including knowledge structure, collaboration networks, and evolving trends-remains poorly characterized. This study aims to map the field using bibliometric analysis. Publications from 2017 to 2025 were retrieved from the Web of Science Core Collection. Bibliometric analyses (publication trends, country/institution collaboration networks, keyword co-occurrence and clustering, co-citation networks, and burst detection) were performed using CiteSpace, VOSviewer, and Scimago Graphica. A total of 390 publications were analyzed. Annual publication output has grown exponentially since 2022. China, the United States, and Italy are the core contributing countries. Research hotspots center on inflammatory responses, oxidative stress, and pollutant exposure. The frontier has shifted from fundamental toxicology toward nanoplastics and specific polymers (e.g., polystyrene) in CVD, as well as their association with clinical outcomes. Emerging foci include cardio-renal comorbidity. To our knowledge, this is the first bibliometric study to systematically map the MNP-CVD research field. The field is moving from mechanistic exploration toward clinical epidemiological research. Future priorities include interdisciplinary collaboration, standardized detection methods, large-scale prospective cohort studies, and mechanism-based targeted interventions. Bibliometric data reflect publication patterns, not causal evidence.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027186","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 Potential Protective Effects of Resveratrol Against Cabazitaxel-Induced Oxidative Stress and Cardiotoxicity in Rats.","authors":"Hadeer Khaled, Ahmed Farag, Ahmed Elfadadny, Takashi Tanaka, Hany Hassan, Zongru Li, Ahmed Mandour, Ryou Tanaka","doi":"10.1007/s12012-026-10126-7","DOIUrl":"10.1007/s12012-026-10126-7","url":null,"abstract":"<p><p>Cabazitaxel, an anti-prostate cancer agent, is associated with dose-dependent cardiotoxicity mediated by oxidative stress. This study investigated cabazitaxel-induced cardiac injury, the utility of intraventricular pressure gradients for early detection, and the potential protective effects of resveratrol. Twenty male Sprague Dawley rats were allocated into four groups: control, therapeutic cabazitaxel (0.5 mg/kg/week, intraperitoneally), toxic cabazitaxel (1.5 mg/kg/week, intraperitoneally), and toxic cabazitaxel + resveratrol (1.5 mg/kg/week cabazitaxel + 10 mg/kg/day resveratrol, intraperitoneally) for 28 days. Cardiac function was assessed via conventional echocardiography, electrocardiography, and intraventricular pressure gradients under anesthesia. Blood samples and heart tissues were collected for further biochemical and histopathological evaluation. Toxic cabazitaxel administration induced significant RR prolongation and bradycardia compared with controls (RR: 0.21 ± 0.02 vs. 0.18 ± 0.02 s; heart rate: 285.88 ± 31.04 vs. 330.40 ± 27.24 bpm), accompanied by aortic dilatation (aortic diameter: 3.73 ± 0.29 vs. 3.28 ± 0.21 mm), reduced acceleration time to ejection time ratio (0.21 ± 0.04 vs. 0.32 ± 0.12), increased derivatives of reactive oxygen metabolites: 394.75 ± 63.47 vs. 324.80 ± 15.56 U.CARR), elevated platelet counts (121.10 ± 26.48 vs. 81.65 ± 6.49 10⁴/µL), decreased hemoglobin levels (14.26 ± 2.02 vs. 17.66 ± 1.014 g/dL), along with structural myocardial damage. Resveratrol co-administration reduced derivatives of reactive oxygen metabolites (372.40 ± 33.02), normalized aortic diameter, and improved acceleration time to ejection time ratio (3.09 ± 0.40 mm; 0.28 ± 0.06), enhanced electrocardiographic parameters (RR: 0.17 ± 0.01 s; heart rate: 352.24 ± 20.567), restored hemoglobin and platelet counts (15.94 ± 1.39 g/dL; 98.38 ± 28.41 10⁴/µL), and preserved myocardial architecture. However, intraventricular pressure gradient indices remained elevated, and persistent thinning of the left ventricular posterior wall at end-diastole and end-systole was observed. These findings suggest that resveratrol partially mitigates cabazitaxel-induced cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13212790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027305","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":"Clinical Characteristics and Outcomes of Heart Failure with Preserved Ejection Fraction Versus Reduced Ejection Fraction in Patients Receiving Anticancer Drugs.","authors":"Yuma Shibutani, Fuka Aoki, Takuro Imaoka, Atsuko Suzuki, Kazuko Tajiri","doi":"10.1007/s12012-026-10133-8","DOIUrl":"10.1007/s12012-026-10133-8","url":null,"abstract":"<p><p>This study aimed to compare prevalence, clinical features, and outcomes between patients with heart failure (HF) with preserved ejection fraction (HFpEF) and those with reduced ejection fraction (HFrEF) who received anticancer drugs. This single-center, retrospective study included 126 patients who developed new-onset HF or worsening HF after starting anticancer drug treatment between April 2018 and December 2023. HFrEF was defined as HF symptoms and signs with left ventricular ejection fraction (LVEF) < 50%, and HFpEF as LVEF ≥ 50%. Among the cohort, 49 patients (39%) had HF with New York Heart Association functional class ≥ 3, and the proportions of HFrEF and HFpEF were similar (61 [48%] vs. 65 [52%], respectively). Patients with HFrEF had a significantly higher history of anthracycline use, whereas fluoropyrimidine or other cytotoxic chemotherapy use was lower. Overall, 84% discontinued or interrupted anticancer therapy after HF onset. There were no significant differences in overall survival (log-rank p = 0.27) or cancer treatment continuation rates (log-rank p = 0.83) between HFpEF and HFrEF. All-cause mortality was associated with anemia (odds ratio [OR]: 3.46, 95% confidence interval [CI]; 1.36-8.82, p = 0.009) and performance status ≥ 3 (OR: 3.13, 95% CI; 1.18-8.26, p = 0.021), but not with LVEF. In patients who developed HF after anticancer treatment, HFrEF and HFpEF occurred at similar rates. There were no significant differences in overall survival or cancer treatment continuation between groups. Anemia and poor performance status, but not LVEF, independently predicted all-cause mortality.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027283","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":"QT Prolongation and Arrhythmias in Cancer Therapy: A Narrative Review of Mechanistic and Clinical Studies.","authors":"Kayode E Ogunniyi, Trie Arni Djunadi, Samuel Abiola Ayedun, Victor Onyenokwe, Oghenevwede Anderson Okuma, Eric Sanji, Andrew Greek","doi":"10.1007/s12012-026-10130-x","DOIUrl":"10.1007/s12012-026-10130-x","url":null,"abstract":"<p><p>Drug-induced QTc prolongation has emerged as a major, preventable cause of malignant ventricular arrhythmias in cancer therapy. This narrative review integrates mechanistic, clinical, and practical insights into QTc prolongation associated with antineoplastic and supportive medications. We outline direct ionic mechanisms, most notably hERG/IKr blockade and PI3K/Akt pathway modulation, as well as indirect contributors, including cytokine-mediated myocarditis, electrolyte disturbances, and structural remodeling. High-risk agents, including arsenic trioxide, vandetanib, nilotinib, sunitinib, and ribociclib, are contrasted with lower-risk alternatives and QT-sparing strategies. Polypharmacy and drug-drug interactions are emphasized as major real-world amplifiers of risk. Among supportive medications, fluoroquinolones, azole antifungals, and certain antiemetics frequently interact with QT-active anticancer agents, whereas beta-lactams, echinocandins, isavuconazole, and palonosetron may represent safer alternatives. We propose a mechanism-to-bedside framework that incorporates baseline ECG and electrolyte assessment, QT-risk stratification, and clear intervention thresholds (QTc ≥ 500 ms or an increase of ≥ 60 ms). Acute management of torsades de pointes, including intravenous magnesium and overdrive pacing, as well as structured hold-and-rechallenge algorithms, is also summarized. Finally, we highlight system-level measures, such as drug interaction stewardship, standardized discharge communication, and clinician education, to shift cardio-oncology practice from reactive arrhythmia management toward anticipatory prevention. This integrative synthesis aims to preserve oncologic efficacy while mitigating arrhythmic risk in modern cancer care.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004696","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":"Doxorubicin-Induced Cardiotoxicity in Breast Cancer: Mechanistic Pathways, Pharmacogenomic Modifiers, and Translational Strategies.","authors":"Chi-Tong Kuok, Hao-Wei Lee, Chen-Yu Huang, Yu-Che Cheng, Shih-Chang Lin, Jiun-Wen Guo","doi":"10.1007/s12012-026-10132-9","DOIUrl":"10.1007/s12012-026-10132-9","url":null,"abstract":"<p><p>Doxorubicin, a prototypical anthracycline, remains an important component of breast cancer therapy, although its use has declined with the availability of effective non-anthracycline regimens and is increasingly restricted to selected high-risk settings. At the same time, anthracyclines continue to serve as first-line therapy for multiple malignancies, including lymphomas, leukemias, and sarcomas, sustaining the broad clinical relevance of anthracycline-associated cardiotoxicity. This timely review synthesizes mechanistic, pharmacogenomic, and translational evidence on doxorubicin-induced cardiovascular toxicity. We highlight the interplay of DNA intercalation, topoisomerase II poisoning, redox cycling, mitochondrial dysfunction, and lipid metabolism as drivers of both anticancer efficacy and myocardial injury. Pharmacogenomic variants such as RARG, SLC28A3, and SLC22A3 (OCT3) modify individual susceptibility, offering investigational, genotype-informed avenues for cardioprotection. Emerging biomarkers-including troponins, sphingolipids, cell-free DNA, and immune signatures-show promise for early detection of cardiac injury. In parallel, tumor-intrinsic and microenvironmental mechanisms contribute to doxorubicin resistance, underscoring the need for integrated strategies that address efficacy and toxicity concurrently. Translational advances include established cardioprotective approaches such as dexrazoxane and liposomal formulations, alongside investigational strategies-including SGLT2 inhibitors, OCT3 blockade, and RARG agonists-that require prospective validation. Complementary efforts to overcome resistance encompass nanomedicine-based delivery, STAT3 inhibition, and RNA-directed therapeutics. By converging molecular mechanisms, pharmacogenomic insights, and biomarker discovery, this review outlines precision strategies to sustain doxorubicin benefit while minimizing cardiovascular harm.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004699","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":"Drug-Induced Noninfectious Myocarditis/Pericarditis: A Real-World Pharmacovigilance Study Using the FAERS Database.","authors":"Shijie Zhao, Weiyi Chen, Chao Tao, Ke Wang, Liuxuan Yang, Ruixiao Li, Meiling Zhou, Jinlu Shang, Xianbin Liu","doi":"10.1007/s12012-026-10129-4","DOIUrl":"10.1007/s12012-026-10129-4","url":null,"abstract":"<p><p>In this pharmacovigilance study, we aimed to identify the primary suspected drugs associated with drug-induced noninfectious myocarditis/pericarditis by analyzing adverse event reports in the FDA Adverse Event Reporting System database from 2004 to 2023. This study utilizes \"Noninfectious Myocarditis/Pericarditis\" as a standardized MedDRA query (SMQ), employing the reporting odds ratio, proportional reporting ratio, and Bayesian Confidence Propagation Neural Network methods at the SMQ and Preferred Term levels to monitor potential drug signals, and provides a comprehensive overview of medications associated with drug-induced noninfectious myocarditis/pericarditis. A total of 21,422 relevant adverse event reports were identified, among which 953 drugs were reported as primary suspects. Disproportionality analysis using the reporting odds ratio, proportional reporting ratio, and Bayesian confidence propagation neural network methods revealed 193, 163, and 176 drugs, respectively, with potential signals of drug-induced noninfectious myocarditis/pericarditis. Notably, clozapine emerged as the most frequently reported drug, followed by nivolumab and pembrolizumab. Immune checkpoint inhibitors used in antitumor therapy represented the highest proportion of the drug category among the top 30 drugs implicated in adverse event reports. Our findings contribute to a better understanding and prevention of myocarditis/pericarditis, offering valuable reference information for clinical practice.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986690","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":"Hexavalent Chromium Exposure Disrupts Cardiac Development in Chicken Embryos Through Oxidative Stress and Activation of TGFβ1/COL3A1 Pathway in Chick Embryos.","authors":"Megha Dave, Selvaraj Jayaraman, Giulia Guerriero, A V Ramachandran, Raktim Mukherjee","doi":"10.1007/s12012-026-10134-7","DOIUrl":"10.1007/s12012-026-10134-7","url":null,"abstract":"<p><p>Hexavalent chromium [Cr(VI)] is a pervasive environmental contaminant with well-documented toxicological effects across biological systems, yet its impact on early cardiac development within ecologically relevant exposure contexts remains insufficiently explored. The present study investigated the effects of in ovo Cr(VI) exposure on cardiac development in chicken embryos, integrating molecular toxicology findings with broader implications for biodiversity conservation and environmental sustainability. Environmental relevance was confirmed by detecting significantly elevated chromium concentrations in eggs collected from industrial regions (0.122-0.202 mg/kg) compared with poultry farm controls. Embryos exposed to 0.7 µg and 1.4 µg Cr(VI) per egg exhibited dose-dependent reductions in survival and crown-rump length, indicating developmental toxicity. Biochemical assessments revealed pronounced oxidative stress, characterized by increased lipid peroxidation (65-84%), substantial glutathione depletion (30-70%), and decreased antioxidant vitamins (A, C, and E), accompanied by reduced activities of key antioxidant enzymes (SOD, CAT, GPx) at embryonic day 14. Elevated serum CK-MB levels confirmed myocardial injury. Molecular analyses demonstrated significant upregulation of TGF-β1 and COL3A1 transcripts, correlating with increased hydroxyproline content and collagen deposition in cardiac tissue, as validated by Sirius Red staining, thereby indicating fibrotic remodeling mediated through the TGF-β1/COL3A1 axis. Collectively, these findings demonstrate that environmentally relevant Cr(VI) exposure disrupts embryonic cardiac development through oxidative and profibrotic mechanisms. The study underscores the ecological risks posed by heavy-metal contamination to avian species and highlights the importance of environmental monitoring and sustainable industrial practices to protect biodiversity and ecosystem health.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986694","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":"Immune Checkpoint Inhibitor-Associated Cardiovascular Toxicity: Mechanisms, Clinical Manifestations, and Clinical Impact.","authors":"Zhengyu Chen, Meijie Zheng, Yuxuan Li, Xiwu Zhang, Jinjin Dou","doi":"10.1007/s12012-026-10131-w","DOIUrl":"10.1007/s12012-026-10131-w","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) represent a class of novel anticancer agents that enhance T cell-mediated recognition and elimination of tumor cells by inhibiting immune checkpoints such as CTLA-4 and PD-1/PD-L1. These therapeutics are widely employed in the treatment of various malignancies, including melanoma and non-small cell lung cancer, and have markedly improved clinical outcomes. However, ICIs are associated with immune-related adverse events (irAEs). Among these, cardiovascular toxicities, though relatively uncommon (occurring in approximately 3.1% of patients receiving monotherapy and 5.8% on combination therapy), are linked with the highest mortality rates. Cardiovascular toxicities associated with ICIs mainly encompass myocarditis (incidence: 1%-2%; mortality: 39.7%-66.0%), pericarditis (case fatality rate: ~13%), and accelerated atherosclerosis. Risk profiles differ across ICI agents; CTLA-4 inhibitors, for example, demonstrate more pronounced and dose-dependent cardiotoxicity, and combination therapies are associated with higher risks compared to monotherapy. The pathogenic mechanisms are attributed to loss of immune tolerance, which involves excessive activation of T cells, triggering autoimmune responses; cross-reactive T cells targeting shared cardiac antigens; and cytokine release storms that promote systemic inflammation. Although advances have been made in the diagnosis and management of cardiovascular toxicities associated with ICIs, several challenges persist. These include an incomplete understanding of the underlying mechanisms and a lack of reliable predictive biomarkers. Research should prioritize elucidating the pathogenic pathways, refining combination therapy regimens, identifying novel therapeutic targets, and developing artificial intelligence (AI)-based predictive models. Such efforts are crucial in mitigating toxicity, enhancing patients' quality of life, and improving long-term outcomes.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980735","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 Integrated Stress Response Protein, eIF2α, Modulates UPR^mt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.","authors":"Kienan P O'Dwyer, Perry E Bauer, Subhankhi Pal, Kathleen Brundage, Sundararajan Venkatesh","doi":"10.1007/s12012-026-10124-9","DOIUrl":"10.1007/s12012-026-10124-9","url":null,"abstract":"<p><p>Doxorubicin (DOX), is an indispensable first-line chemotherapeutic. Despite this first-line indication, clinical use of DOX is limited by severe, off-target, and often irreversible cardiotoxicity. DOX induces cytotoxicity in rapidly dividing cancer cells via inhibition of Topoisomerase IIα. However, the underlying mechanisms by which DOX causes cell death in non-replicative, terminally differentiated cardiomyocytes remain poorly understood. Emerging evidence suggests that mitochondrial uptake of DOX is contributory to cardiotoxicity. Whether mitochondrial stress pathways, including the mitochondrial unfolded protein response (UPR^mt), are activated and critical for mediating DOX cardiotoxicity is poorly understood. Moreover, whether phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), a mediator of the Integrated Stress Response, regulates potential UPR^mt signaling during DOX treatment is also unknown. Here, using human AC-16 cardiac cells, we examined the role of eIF2α phosphorylation during DOX treatment. Our data suggest that DOX triggers a transient increase in eIF2α phosphorylation, followed by a progressive decline. Further, knockdown of eIF2α decreased key transcriptional regulators of UPR^mt signaling such as C/EBP Homologous Protein and ATF5, blunted the induction of UPR^mt genes (AFG3L2, CLPP, HSPA9, HSPD1, LONP1, SPG7), and aggravated DOX induced cytotoxicity. Together, these findings identify eIF2α as a critical upstream regulator of UPR^mt signaling, and suggest that activation of the UPR^mt may confer cardio-protection against DOX-induced mitochondrial stress in human cardiac cells.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970659","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}