Heart failure with preserved ejection fraction (HFpEF) accounts for 50

Platelets are key mediators of hemostasis and thrombosis. Acid-sensing ion channel 3 (ASIC3), a proton-gated cation channel, can be directly activated at pH 7.4 by the synthetic compound 2-guanidine-4-methylquinazoline (GMQ). However, the role of GMQ in platelet activation and its potential dependence on ASIC3 remain unclear. This study investigated whether GMQ modulates platelet function at physiological pH (7.4), whether this regulation is mediated by ASIC3, and what the underlying molecular mechanisms are. We found that GMQ significantly suppressed platelet activation in both human and murine platelets at pH 7.4 and attenuated thrombus formation and hemostatic function in mice. ASIC3 was confirmed to be functionally expressed in human and murine platelets. Although ASIC3 deficiency did not affect basal platelet characteristics or platelet activation at pH 7.4, it markedly diminished GMQ-mediated suppression of platelet activation, thrombosis, and hemostasis. Mechanistically, GMQ enhanced cyclic adenosine monophosphate (cAMP) production and promoted protein kinase A (PKA) Thr197 phosphorylation through interaction with ASIC3-cyclase-associated protein 1 (CAP1), thereby suppressing platelet function. Overall, this study demonstrates, for the first time, that GMQ inhibits platelet activation and thrombosis under physiological pH by targeting ASIC3 and activating the CAP1/ cAMP/PKA signaling pathway. These findings suggest that targeting the non-proton domain of ASIC3 at physiological pH may represent a novel and promising antiplatelet therapeutic strategy.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Platelet activation plays a critical role in arterial thrombotic events such as myocardial infarction. Although antiplatelet drugs are standard therapies, they are associated with risks including bleeding, gastrointestinal adverse effects, and drug resistance. Furthermore, substantial inter-individual variability in patient responses underscores the need for personalized antiplatelet regimens. These factors emphasize the importance of screening for optimal antiplatelet drugs and drug combinations tailored to individual patients. However, traditional platelet detection assays are reagent-hungry and low-throughput, making them unsuitable for high-throughput screening of antiplatelet agents. Here, we present the C-chip, a high-throughput platform for on-chip parallel screening of antiplatelet drug combinations. The C-chip miniaturizes individual screening reactions into picoliter-volume, color-coded droplets, enabling the generation of thousands of screening data points in a single experiment. We demonstrate that the C-chip can effectively identify the optimal combinations of three clinically relevant antiplatelet drugs: Aspirin, Tirofiban, and Ticagrelor. We further applied this platform to identify optimal drug combinations for five healthy volunteers, revealing marked inter-individual variability in antiplatelet drug responses.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, in which the role of lipophagy, a selective autophagic process degrading lipid droplets (LDs), remains poorly characterized. This study investigated lipophagy and its key regulator, OSBPL10, in PDAC progression. Through immunofluorescence analysis of patient samples, transgenic mouse tissues, and cell lines, we find that lipophagy is elevated in PDAC and correlates with poor prognosis. Single-cell transcriptomic analysis identified OSBPL10 as a critical lipophagy regulator and an independent clinicopathological indicator. Functional assays, including orthotopic and subcutaneous xenografts, demonstrated that OSBPL10 promotes tumor growth. Mechanistically, OSBPL10 functionally cooperates with VAPA/VAPB to facilitate rapid lysosomal repair via ATG2A, thereby promoting lipophagy and lipid mobilization. Inhibition of lysosomal function abrogated the pro-lipophagic and pro-tumorigenic effects of OSBPL10. Collectively, our findings demonstrate that upregulated OSBPL10 drives PDAC progression by enhancing lipophagy through ATG2A-mediated rapid lysosomal repair, highlighting OSBPL10 as a potential therapeutic target in PDAC.

Extrachromosomal circular DNAs (eccDNAs) are well-established drivers of tumorigenesis, yet their landscape and functional significance in human heart failure (HF) remain largely unknown. Using Tn5 transposase-based sequencing, we comprehensively profiled plasma eccDNAs from healthy controls and HF patients with myocardial ischemia (MI-HF) or non-myocardial ischemia (NMI-HF). Bioinformatics was employed to probe their chromosomal origins, genomic features, and potential roles in the development of HF. Circular structures of candidate eccDNAs were validated by inward and outward PCR followed by Sanger sequencing. Their clinical prognostic value was assessed by Kaplan–Meier and Cox regression analyses in a patient cohort. Most plasma eccDNAs were shorter than 1 kb and originated from all chromosomes, with selective enrichment from specific genomic regions including 5′ UTRs, CpG islands, and Alu elements. Characteristic nucleotide repeats were identified at eccDNA junction sites. The circular structure of eccDNAs was confirmed. Furthermore, we discovered that the eccDNA ENPP1circle exon 25 was specifically detected in MI-HF patients. Its presence was significantly associated with a higher incidence of major adverse cardiac events (MACEs), and it served as an independent prognostic biomarker in multivariate analysis. This study delineates the first detailed landscape of plasma eccDNAs in HF and reveals their potential as noninvasive biomarkers for risk stratification. Our findings lay a crucial foundation for future research into eccDNA biology and their translational applications in cardiovascular disease.

BACKGROUND:Treatments for heart failure with preserved ejection fraction (HFpEF) remain inconclusive. AIMS:We aim to explore in this prospective and observational cohort study how combined therapy with sodium-dependent glucose transporter 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), angiotensin receptor-neprilysin inhibitor (ARNI), or mineralocorticoid receptor antagonists (MRA) impact clinical outcomes in HFpEF patients with type 2 diabetes mellitus (T2DM). METHODS:We enrolled 1445 HFpEF patients with T2DM from a prospective cohort between October 2018 and October 2022. The patients were divided into five groups based on their medications at 3 months after discharge: defined as a combination of SGLT2i, GLP-1RA, ARNI, and MRA. The primary outcome is major adverse cardiovascular (CV) events (MACEs), corresponding to the CV mortality and/or HF rehospitalization. The secondary outcome is CV mortality as well as left ventricular ejection fraction (LVEF) change or HF category transition. RESULTS:During a median follow-up period of 54 (27-75) months, participants with quadruple combination showed the most benefits, corresponding to MACEs (79/174; P <0.001), CV mortality (46/174; P = 0.03), LVEF change, or HF transitions. Quadruple combination was a protective factor for MACEs, while higher N-terminal pro-B-type natriuretic peptide level was an independent risk factor. For participants with LVEF less than 60%, quadruple combination reduced the incidence of composite endpoint events compared to those with LVEF over 60%. CONCLUSIONS:Quadruple combination therapy with SGLT2i, GLP-1RA, ARNI, and MRA in HFpEF patients with T2DM was associated with favorable clinical outcomes, especially in participants with LVEF less than 60%.

This study aimed to evaluate the association between LAA metabolic parameters—particularly lactic acid, glucose, and calcium—and spontaneous echo contrast, and to develop and externally validate a multivariable prediction model incorporating these indicators. Consecutive patients with AF undergoing radiofrequency catheter ablation and/or left atrial appendage occlusion were retrospectively enrolled. All patients underwent preprocedural transesophageal echocardiography with direct LAA blood sampling for metabolic analysis. An internal cohort was used for feature selection by LASSO regression and multivariable logistic regression. Model performance was assessed using ROC analysis, calibration, and decision curve analysis, with external validation in an independent cohort. A total of 272 patients were included in the internal cohort, among whom 96 (35.3

Background: The role of euthyroid hormone levels in clinical outcomes after drug-coated balloon (DCB) angioplasty in patients with coronary heart disease (CHD) remains unclear. Thus, this study aimed to explore the relationship between thyroid function and the risk of restenosis at one year, as well as the prognosis over five years in euthyroid patients with CHD following DCB angioplasty. Methods: This prospective study evaluated 189 euthyroid CHD patients who underwent successful DCB angioplasty. Coronary angiographic follow-up was performed 9–12 months post-procedure to assess the status of target lesions, with restenosis defined as ≥50% reduction in luminal diameter. All patients underwent five-year clinical follow-ups, during which major adverse cardiovascular events (MACEs) were recorded. Results: Following angiographic follow-ups, patients were categorized into two groups: those with restenosis (n = 66) and those without (n = 123). At baseline and during the follow-up, the restenosis group demonstrated significantly higher levels of thyroid-stimulating hormone (TSH), lymphocytes, hemoglobin A1c (HbA1c), lipoprotein(a), and platelet count, along with lower free triiodothyronine (FT3) levels. Multivariable logistic regression analysis revealed that the TSH levels both at the baseline (odds ratio (OR) 1.607, 95% confidence interval (CI) 1.238–2.085, p < 0.001) and angiographic follow-up (OR 2.970, 95% CI 2.000–4.411, p < 0.001) were independently associated with an increased risk of post-DCB restenosis. Furthermore, patients in the high TSH tertile had a 90% increased risk of MACEs during the 5-year follow-up period (hazard ratio (HR) 1.922, 95% CI 1.343–2.750, p < 0.001) compared with those in the low TSH tertile. Conclusions: A high-normal TSH level within the euthyroid range was strongly associated with an increased 1-year restenosis risk and decreased 5-year MACE-free survival following DCB angioplasty in CHD patients.

Ferroptosis significantly contributes to myocardial injury in Type 2 Diabetes Mellitus (T2DM). Liver X Receptor (LXR) and Retinoid X Receptor (RXR) play crucial roles in lipid metabolism and inflammation, but their involvement in regulating ferroptosis in diabetic cardiomyocytes is not fully understood. High-fat diet/streptozotocin-induced T2DM mouse models and high glucose and high fat (HG)-exposed cardiomyocytes were used to assess the impact of LXR activation on myocardial injury and ferroptosis. The study also examined the role of the ROS/AMPK/Nrf2 pathway and the effect of LXR/RXR activation on Calpain1 and Calpastatin expression. Activation of LXR was shown to reduce myocardial injury susceptibility by protecting cardiomyocytes from ferroptosis. This protection occurs via relieving HG-induced ROS-mediated suppression of the AMPK/Nrf2 axis, preventing ferroptosis under hyperglycemic conditions. Moreover, pharmacological activation of LXR/RXR heterodimers was found to alleviate cardiomyocyte injury by downregulating Calpain1, a protein that induces ferroptosis through mitochondrial pathways. Mechanistically, LXR/RXR resulted in the transcriptional activation of Calpastatin, which in turn inhibited Calpain1 expression. This inhibition of Calpain1 led to reduction of mitochondrial ROS overproduction, thereby disinhibiting the AMPK/Nrf2 pathway, significantly reducing ferroptosis and myocardial injury. LXR activation protects against T2DM-induced myocardial injury by inhibiting ferroptosis, particularly through the LXR/RXR-Calpastatin-Calpain1 axis, offering a potential therapeutic strategy for T2DM-related heart damage.

Peri-device leakage (PDL) is one of the major complications of left atrial appendage closure (LAAC). However, there is a lack of predictive models in clinical practice. The aim of this study was to develop and validate a prediction model for PDLs after LAAC based on preoperative CT and CT-based radiomic features. This retrospective cohort study included 100 patients with nonvalvular atrial fibrillation who underwent LAAC between August 2023 and August 2024 at two centers. A clinical model was constructed via binary logistic regression with clinical information, and a radiomic model was constructed via conventional CT measurements and radiomic features. A combined model was also constructed by combining clinical information and imaging features. The performance of all the models was evaluated and compared, and internal validation was performed via the bootstrap method. Multivariate analysis revealed that the least axis length, larger diameter, and hypertension grade 3 were independent risk factors for PDLs. The combined model constructed based on these three factors (AUC: 0.796, 95

Background Heart failure (HF) is a currently incurable disorder that increases the risk for stroke and sudden cardiac death. Shortened telomeres have been linked to the development of cardiomyocyte abnormalities and dysfunction, and telomere reprotection has become a favourable strategy for designing novel heart failure therapies. This study aims to design a pan-HF gene therapy where modified human telomerase expression is driven by cardiac troponin promoter and to evaluate cardiac protection. Methods Telomere shortening was determined in cardiomyocytes from Macaca fascicularis (cynomolgus monkey) and patients with HF by quantitative fluorescence in situ hybridisation (Q-FISH) assays. We bioengineered a catalytic inactivation and nuclear retaining modified human TERT (telomerase reverse transcriptase) gene therapy (AAV9-modhTERTY707F, D868A). In transverse aortic constriction (TAC)-induced WT and myocardial p53 deficient (p53CKO) mice HF model, as well as Ang II-induced human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we evaluate cardiac protection of modhTERT via echocardiography, RNA-sequence, Western blotting, Proteome Profiler Mouse XL Cytokine Array panel, RT-qPCR, transmission electron microscopy, and immunofluorescence. Findings AAV9-modhTERTY707F, D868A reversed cardiac function decline and prevented onset of cardiac fibrosis in TAC-induced HF murine. At cellular level, modhTERT alleviated contractile dysfunction and aberrant calcium handling in cardiomyocytes isolated from TAC hearts and prevented Ang II-stimulated hiPSC-CMs hypertrophy. Overexpression of modhTERT blocked telomeric DNA damage response (DDR) and p53 ser15-phosphorylation. Myocardial chronic inflammation and reactive oxygen species (ROS) levels were reverted by modhTERT overexpression. Additionally, modhTERT rescued mitochondrial ultrastructure, increased mitochondrial DNA (mtDNA) copy, and restored ATP production through restoration of PGC-1 α and TFAM expression. Interpretation We provide evidence that telomere re-protection confers cardiac protection and may serve as a potential gene therapeutic option for treating heart failure. Funding This research was supported by the National Natural Science Foundation of China (82070248, 82300282, 82300476), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (0900000024), 2023 Shanghai Action Plan for Promoting Scientific and Technological Innovation and Industrial Development of Gene Therapy (23J11900600).

Aims Heart failure (HF) remains a highly prevalent condition with current therapeutic options, 5-year survival remains at 50%. Diseased cardiomyocytes have been demonstrated to exhibit telomeric shortening and through DNA damage response (DDR) activation leads to mitochondria dysfunction. How the orchestration between nuclear and mitochondrial transcription systems regulates myocardial function remains elusive. The aim of this study is to test if myocardial telomere re-protection can restore nuclear-mitochondrial balance and offer a strategy for treating HF.Methods and results To re-protect telomeric ends, we designed an adeno-associated virus 9 (AAV9)-mediated delivery system carrying modified human telomerase protein (modhTERTY707F, D868A, JV101) under cardiac troponin T promoter regulation. The modhTERT is engineered to be catalytic inactive, nuclear localized, and bind to telomeric ends to turn off DDR. Telomeric repeat amplification protocol and quantitative fluorescence in situ hybridization assays were used to demonstrate loss of enzymatic function and localization of JV101. Using TPP1-knock out (TPP1KO) U2OS (telomerase-deficient) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) lines generated by CRISPR/Cas9 genome editing, we demonstrated that JV101 is recruited by TPP1 through TEL patch to telomeric ends. JV101 restored cardiac function in both Ang II infusion and myocardial ischaemia-reperfusion HF models and in Ang II-stressed hiPSC-CMs. RNA-Seq data suggests that uncapped telomeres activated p53 and using myocardial p53 deficient (p53cKO) mice we demonstrate that telomere-p53-mitochondrial dysfunction is the main signalling pathway driving HF. Molecularly, JV101 treatment silenced p53, rescued both mitochondrial biogenesis as well as prevented mitochondrial DNA N6-methyladenine (m6A) methylation.Conclusion Our work establishes the role of telomere-mitochondria DNA signalling during HF progression and provides proof-of-concept of telomere-targeting gene therapy to restore cardiac function.

INTRODUCTION:Atrial fibrillation (AF), with a prevalence of 1-2%, is the most common cardiac arrhythmia. AF is associated with a fivefold increased risk of cardioembolic events; approximately 20% of all strokes are caused by AF. Pulmonary vein isolation (PVI) has become the first-line treatment for AF. However, PVI cannot eliminate the residual stroke risk. Current guidelines recommend that anticoagulation be continued in this specific group of patients, regardless of the presence or absence of AF. In this large AF population post-PVI, who are considered to be in an earlier stage of AF, it is unknown whether left atrial appendage closure (LAAC) offers an alternative to direct oral anticoagulant (DOAC) therapy. METHODS AND ANALYSIS:The trial will be a prospective, randomised, multicentre non-inferiority study comparing two treatment strategies in AF patients after atrial ablation. Patients will be randomly assigned to either percutaneous LAAC (group A) or DOAC treatment (group B) in a 1:1 ratio; both sequential and concomitant planned ablation with or without LAAC are accepted. Randomisation will be conducted using web-based randomisation software. A total of 1012 participants (506 patients per group) will be enrolled. The primary effectiveness measure will be the occurrence of any of the specified events within 24 months after randomisation: stroke/transient ischaemic attack/systemic thromboembolism, cerebral haemorrhage, other major haemorrhages (Bleeding Academic Research Consortium ≥2), cardiovascular mortality and all-cause mortality. ETHICS AND DISSEMINATION:The study was approved by the Ethical Review Board of Shanghai Chest Hospital, China (KS(Y)20287). Written informed consent will be obtained from all participants. The trial will follow the Declaration of Helsinki and Good Clinical Practice. Confidentiality will be maintained with anonymised, securely stored data. Findings will be disseminated through peer-reviewed publications and conferences. TRIAL REGISTRATION NUMBER:ChiCTR2000036538.

Incomplete endothelialization (IDE) of left atrial appendage closure (LAAC) devices increases the risk of device-related thrombosis (DRT) and stroke. Insulin resistance (IR) may contribute to IDE by impairing endothelial function, but its role remains unclear. This study aimed to investigate the association between IR markers and IDE and develop a predictive model for identifying high-risk patients. This retrospective observational study included 168 patients with nonvalvular atrial fibrillation (AF) who underwent successful LAAC at Shanghai Ninth People’s Hospital between January 2022 and December 2023. IDE was assessed using transesophageal echocardiography (TEE) and cardiac computed tomography angiography (CCTA) at 6 months post-procedure. IR was evaluated using the triglyceride-glucose (TyG) index, triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-c) ratio, and metabolic score for insulin resistance (METs-IR). Logistic regression analysis was performed to identify independent predictors of IDE, and a predictive model was constructed. Among the 168 patients included in the analysis, 43 (25.5

Shorter leukocyte telomere length (LTL) is associated with aging-related cardiovascular diseases, but its relationship with heart failure with preserved ejection fraction (HFpEF) in high-risk Chinese patients with hypertension under 65 years remains unclear. In this observational prospective study, we investigated 646 patients with hypertension aged < 65 years with diabetes, coronary heart disease (CHD), or ≥ 3 cardiovascular risk factors. Baseline assessments included clinical evaluation, measurement of aging markers (LTL and mitochondrial DNA copy number) and echocardiography. Participants underwent scheduled quarterly follow-up for 5 years, with documentation of major adverse cardiovascular events (MACEs), including cardiovascular mortality, myocardial infarction, ischemia-driven revascularization, stroke and heart failure hospitalization. At the final follow-up visit, the evaluation for HFpEF was performed through echocardiography and plasma B-type natriuretic peptide (BNP) measurement. Participants were stratified by LTL tertiles: long (> 79.89; n = 216), mid (58.49–79.89; n = 214), and short (< 58.49; n = 216). Compared with the long and mid LTL groups, the short LTL group had a higher prevalence of male, smoking, hyperlipidemia, diabetes, and CHD, along with elevated blood pressure and fasting blood glucose, but lower mitochondrial DNA copy number (all P < 0.05). At 5-year follow-up, HFpEF prevalence increased with shorter LTL (15.7

Introduction The purpose of this study is to evaluate the safety and efficacy of two different antithrombotic strategies, dual antiplatelet therapy (DAPT, aspirin and ticagrelor) and direct oral anticoagulant (DOAC, rivaroxaban), after left atrial appendage closure (LAAC) using the LACbes occluder.Methods and analysis This study is a prospective, randomised, controlled and multicentre clinical trial that will compare the clinical efficacy of antiplatelet and anticoagulation therapy after LAAC with the LACbes occluder. It is planned to enrol 296 subjects with non-valvular atrial fibrillation (NVAF) who complete transcatheter closure of the left atrial appendage successfully. All subjects who pass the screening process and sign informed consent forms will be randomised in a 1:1 ratio to the DAPT group (aspirin 100 mg/day and ticagrelor 90 mg two times a day) or the DOAC group (rivaroxaban 15 mg/day). Baseline data within 24 hours after the operation and follow-up information at 3, 6 and 12 months will be recorded to investigate the difference in the incidence of device-related thrombosis, clinical thrombotic events, bleeding and other adverse events.Ethics and dissemination Ethics approval has been obtained from the Ethics Committee of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Approval number SH9H-2022-T426-1). The protocol (Version: V1, 20230105) has also been submitted and approved by the institutional ethics committee at each participating centre. Results are expected in 2025 and will be disseminated through peer-reviewed journals and presentations at national and international conferences.Trial registration number ChiCTR2100046712.Trial registration name Different antithrombotic strategies after left atrial appendage closure with the LACbes occluder.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce incidence of cardiovascular events in type 2 diabetes (T2D) patients. Yet, the impact of GLP-1RAs on coronary lesion progression and cardiovascular outcomes after coronary stent implantation remains unclear. We aimed to investigate the effects of GLP-1RAs on coronary lesion progression and major adverse cardiovascular events (MACEs) after percutaneous coronary intervention (PCI). This prospective cohort study enrolled 1664 patients with T2D who underwent PCI from January 2020 to March 2024. Matched GLP-1RAs-treated and non-treated cohorts were formed using the propensity score matching method. The primary endpoint was the incidence of MACEs (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure). Secondary endpoints included in-stent restenosis and non-target lesion progression. Two 131-patient cohorts with balanced baseline characteristics were formed by propensity score matching. During the median follow-up period of 20 months (ranging from 6 to 48 months), the incidence of MACEs was significantly lower in the GLP-1RA group (7.63%)compared to the control group (19.85%) (HR 0.444; 95%CI, 0.215-0.918; P = 0.024). During a median follow-up period of 12 months, 79.39% (104/131) of patients in the control group and 82.44% (108/131) of patients in the GLP-1RA group successfully underwent coronary angiography follow-up. The incidence of in-stent restenosis was 2.78% (3/108) in the GLP-1RA group and 11.54% (12/104) in the control group (P = 0.028). Non-target lesion progression was found in 10.19% (11/108) patient of the GLP-1RA group and 22.12% (23/104) in the control group (P = 0.037). Notable disparities were observed between the two groups regarding improvements of BMI, SBP, HbA1c, LDL-C, CRP. GLP-1RAs significantly reduced the incidence of MACEs and coronary lesion progression in patients with T2D after coronary stent implantation. These findings suggest that GLP-1RAs may have beneficial effects on cardiovascular outcomes and coronary artery disease progression in this population.

Doxorubicin, an anthracycline commonly used for treating cancer patients, is known for its cardiotoxic side-effects. Although dose-dependent, but susceptibility remains variable among patients, and childhood-exposure-adult-onset remains challenging. Besides topoisomerase toxicity, Doxorubicin is also toxic to the mitochondria yet the underlying late onset mechanism remains elusive. Here, it is observed that the mitochondrial copy number in PBMCs of patients treated with anthracycline chemotherapy is negatively correlated with the change in plasma BNP levels after treatment. Isogenic hiPSC-CMs are generated with high, norm, and low mitochondrial copy numbers using mitochondrial transplantation and the YFP-Parkin system. Remarkably, lower mitochondria copy number translates to lower IC50, suggesting increased susceptibility. Mitochondria supplementation by intramyocardial injection prevents doxorubicin induced heart failure. Mechanistically, doxorubicin treatment leads to mPTP opening and mitochondrial DNA (mtDNA) leakage. This mtDNA leakage event activates the cGAS-STING pathway and drives inflammation and myocardial senescence. Cardiomyocyte-specific knockout of Sting (Myh6-Cre/Stingflox/flox; StingCKO) and over expression of mitochondrial tagged DNase1 in mice partially rescue doxorubicin-induced cardiac dysfunction. In conclusion, the work establishes a negative correlation between cardiomyocyte mitochondrial copy number and doxorubicin toxicity. Molecularly, it is demonstrated that mtDNA leakage activates cGAS-STING pathway and accelerates myocardial dysfunction. These insights offer new co-administration strategies for cancer patients.