Case report: A sustained survival benefit of third-line immunotherapy for refractory thymic carcinoma.

Thymic carcinoma (TC) is an uncommon type of thymic epithelial tumors. Patients with relapsed or refractory TCs have a poor prognosis. Immune checkpoint inhibitor monotherapy can be applied as a second-line treatment for such cases. This study reported a TC patient who did not respond to conventional chemotherapy and radiotherapy but achieved prolonged partial remission lasting 17 months following the third-line treatment with anti-programmed cell death-1 inhibitor sintilimab. This patient did not experience any serious side effects associated with sintilimab treatment. The above results demonstrated that sintilimab could be a feasible therapeutic option for refractory TC patients.

Ferroptosis in the adjuvant treatment of lung cancer-the potential of selected botanical drugs and isolated metabolites.

Ferroptosis represents a distinct form of cell death that is not associated with necrosis, autophagy, apoptosis, or pyroptosis. It is characterised by intracellular iron-dependent lipid peroxidation. The current literature indicates that a number of botanical drugs and isolated metabolites can modulate ferroptosis, thereby exerting inhibitory effects on lung cancer cells or animal models. The aim of this review is to elucidate the mechanisms through which botanical drugs and isolated metabolites regulate ferroptosis in the context of lung cancer, thereby providing potential insights into lung cancer treatment. It is crucial to highlight that these preclinical findings should not be interpreted as evidence that these treatments can be immediately translated into clinical applications. In the future, we will continue to study the pharmacology, pharmacokinetics and toxicology of these drugs, as well as evaluating their efficacy and safety in clinical trials, with the aim of providing new approaches to the development of new agents for the treatment of lung cancer.

LncRNA MALAT-1 modulates EGFR-TKI resistance in lung adenocarcinoma cells by downregulating miR-125.

Molecular targeted therapy resistance remains a major challenge in treating lung adenocarcinoma (LUAD). The resistance of Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitor) plays a dominant role in molecular targeted therapy. Our previous research demonstrated the role of MALAT-1 (Metastasis-associated lung adenocarcinoma transcript 1) in the formation of Erlotinib-resistant LUAD cells. This study aims to uncover the mechanism of MALAT-1 overexpression in Erlotinib-resistant LUAD cells. The RT2 LncRNA PCR array system was used to explore MALAT-1 regulation in Erlotinib-resistant LUAD cells through patient serum analysis. Dual luciferase reporter experiments confirmed the binding between MALAT-1 and miR-125, leading to regulation of miR-125 expression. Functional assays were performed to elucidate the impact of MALAT1 on modulating drug resistance, growth, and Epithelial-mesenchymal transition (EMT, Epithelial-mesenchymal transition) in both parental and Erlotinib-resistant LUAD cells. The investigation unveiled the mechanism underlying the competing endogenous RNA (ceRNA, competing endogenouse RNA) pathway. MALAT1 exerted its regulatory effect on miR-125 as a competing endogenous RNA (ceRNA). Moreover, MALAT1 played a role in modulating the sensitivity of LUAD cells to Erlotinib. Rab25 was identified as the direct target of miR-125 and mediated the functional effects of MALAT1 in Erlotinib-resistant LUAD cells. In conclusion, our study reveals overexpress MALAT-1 cause the drug resistance of EGFR-TKIs in non-small cell lung cancer (NSCLC) through the MALAT-1/miR-125/Rab25 axis. These findings present a potential novel therapeutic target and perspective for the treatment of LUAD.

CircCDC42-encoded CDC42-165aa regulates macrophage pyroptosis in Klebsiella pneumoniae infection through Pyrin inflammasome activation.

The circular RNA (circRNA) family is a group of endogenous non-coding RNAs (ncRNAs) that have critical functions in multiple physiological and pathological processes, including inflammation, cancer, and cardiovascular diseases. However, their roles in regulating innate immune responses remain unclear. Here, we define Cell division cycle 42 (CDC42)-165aa, a protein encoded by circRNA circCDC42, which is overexpressed in Klebsiella pneumoniae (KP)-infected alveolar macrophages. High levels of CDC42-165aa induces the hyperactivation of Pyrin inflammasomes and aggravates alveolar macrophage pyroptosis, while the inhibition of CDC42-165aa reduces lung injury in mice after KP infection by inhibiting Pyrin inflammasome-mediated pyroptosis. Overall, these results demonstrate that CDC42-165aa stimulates Pyrin inflammasome by inhibiting CDC42 GTPase activation and provides a potential clinical target for pathogenic bacterial infection in clinical practice.

Gradient-concentration RuCo electrocatalyst for efficient and stable electroreduction of nitrate into ammonia.

Electrocatalytic nitrate reduction to ammonia holds great promise for developing green technologies for electrochemical ammonia energy conversion and storage. Considering that real nitrate resources often exhibit low concentrations, it is challenging to achieve high activity in low-concentration nitrate solutions due to the competing reaction of the hydrogen evolution reaction, let alone considering the catalyst lifetime. Herein, we present a high nitrate reduction performance electrocatalyst based on a Co nanosheet structure with a gradient dispersion of Ru, which yields a high NH3 Faraday efficiency of over 93% at an industrially relevant NH3 current density of 1.0 A/cm2 in 2000 ppm NO3- electrolyte, while maintaining good stability for 720 h under -300 mA/cm2. The electrocatalyst maintains high activity even in 62 ppm NO3- electrolyte. Electrochemical studies, density functional theory, electrochemical in situ Raman, and Fourier-transformed infrared spectroscopy confirm that the gradient concentration design of the catalyst reduces the reaction energy barrier to improve its activity and suppresses the catalyst evolution caused by the expansion of the Co lattice to enhance its stability. The gradient-driven design in this work provides a direction for improving the performance of electrocatalytic nitrate reduction to ammonia.

Differentiation of Cis/trans-geometrical isomers in long-chain unsaturated fatty acids based on ion mobility and theoretical calculations.

In recent years, fatty acids containing conjugated CCs have attracted extensive research attention due to their biological activities against human diseases. However, their differentiation is challenging. This study developed a comprehensive analytical solution to accurately differentiate cis/trans-fatty acid isomers using ion mobility mass spectrometry (IM-MS) and theoretical calculations. Cis/trans-fatty acids were mobility-differentiated via simple complexation with 1,5,9-triazacyclododecane (9C3N) or 1,4,8,11-tetraazacyclotetradecane (10C4N) and metal ions, obtaining baseline separation with a peak-to-peak resolution of 0.35-0.92. Moreover, the conformation of the complexes was optimized theoretically, revealing different binding modes between the cis/trans-fatty acid-9C3N/10C4N-metal ion systems, yielding in-depth structural data on the complexes and elucidating the principles of mobility separation. Furthermore, the proposed method was assessed in terms of quantification, accuracy, and precision repeatability. Finally, the method was applied to analyze oil samples. Given its simplicity, speed, and lack of chemical derivatization or chromatographic separation, this technique has potential applications in food analysis.

NR0B2 re-educates myeloid immune cells to reduce regulatory T cell expansion and progression of breast and other solid tumors.

Although survival from breast cancer has dramatically increased, many will develop recurrent, metastatic disease. Unfortunately, survival for this stage of disease remains very low. Activating the immune system has incredible promise since it has the potential to be curative. However, immune checkpoint blockade (ICB) which works through T cells has been largely disappointing for metastatic breast cancer. One reason for this is a suppressive myeloid immune compartment that is unaffected by ICB. Cholesterol metabolism and proteins involved in cholesterol homeostasis play important regulatory roles in myeloid cells. Here, we demonstrate that NR0B2, a nuclear receptor involved in negative feedback of cholesterol metabolism, works in several myeloid cell types to impair subsequent expansion of regulatory T cells (Tregs); Tregs being a subset known to be highly immune suppressive and associated with poor therapeutic response. Within myeloid cells, NR0B2 serves to decrease many aspects of the inflammasome, ultimately resulting in decreased IL1ß; IL1ß driving Treg expansion. Importantly, mice lacking NR0B2 exhibit accelerated tumor growth. Thus, NR0B2 represents an important node in myeloid cells dictating ensuing Treg expansion and tumor growth, thereby representing a novel therapeutic target to re-educate these cells, having impact across different solid tumor types. Indeed, a paper co-published in this issue demonstrates the therapeutic utility of targeting NR0B2.

Development of NR0B2 as a therapeutic target for the re-education of tumor associated myeloid cells.

Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of Tregs. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of Treg expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.

Sleep disturbance and internalizing symptoms in adolescents: a moderated mediation model of self-control and mindfulness.

OBJECTIVES: Despite accumulating evidence regarding the impact of sleep disturbance on internalizing symptoms among adolescents, the underlying psychological mechanisms remain inadequately explored. This study aimed to investigate a conceptual framework elucidating how sleep disturbance influences internalizing symptoms in adolescents through the mediating role of self-control, with mindfulness as a moderator. METHODS: In this cross-sectional study, 1876 Chinese adolescents (Mage = 14.88 years, SD = 1.47 years, range = 12-19 years, 44.7% boys) completed the Youth Self-Rating Insomnia Scale (YSIS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Brief Self-control Scale (BSCS), and Mindful Attention Awareness Scale-Children (MAAS-C) to provide data on sleep-related variables, internalizing symptoms (anxiety and depression), self-control, and mindfulness, respectively. The PROCESS macro for SPSS was applied to perform moderated mediation analysis. RESULTS: Sleep disturbance demonstrated a significant positive correlation with internalizing symptoms in adolescents, including anxiety (ß = 0.481, p < 0.001) and depression (ß = 0.543, p < 0.001). Self-control served as a mediator between sleep disturbance and two forms of internalizing symptoms. Moreover, mindfulness moderated the pathways from self-control to internalizing symptoms (for anxiety symptoms: ß = 0.007, p < 0.001; for depression symptoms: ß = 0.006, p < 0.001), and the mediating relationships were weaker for adolescents exhibiting higher levels of mindfulness. CONCLUSIONS: Our findings enhance understanding of the impact, pathways, and influencing factors of sleep disturbance on adolescent internalizing symptoms, suggesting the importance of enhancing mindfulness levels in addressing self-control deficits and subsequently reducing internalizing symptoms among adolescents.

Negative life events and sleep disturbance among adolescents: Intolerance of uncertainty as mediator and moderator.

BACKGROUND: While negative life events (NLEs) have been linked to an increased risk of sleep disturbance among adolescents, the mechanisms of this impact still lack further examination. The current study aimed to explore whether intolerance of uncertainty (IU), a dispositional transdiagnostic vulnerability factor for psychopathology, could act as a mediator and/or moderator in the link from NLEs to sleep disturbance. METHODS: A longitudinal nested subsample of 54,240 Chinese adolescents (aged 9-19) were surveyed at baseline (Timepoint 1) and six months later (Timepoint 2). They completed questionnaires to assess their IU, NLEs, sleep disturbance and sociodemographic characteristics. Mediation and moderation analyses were conducted to test our hypotheses. RESULTS: Upon adjusting for covariates, IU was found to mediate the relationship between NLEs and residual changes in sleep disturbance over a six-month period, with the mediation effect accounting for 31.8%. Additionally, the moderating role of IU in this relationship was also identified, suggesting that a high level of IU exacerbated the effect of NLEs on sleep disturbance. CONCLUSIONS: In conclusion, our findings shed light on the dual roles of IU in the link from NLEs to sleep disturbance, holding significant practical implications for preventing and intervening in sleep disturbance among adolescents. To mitigate the risk of sleep disturbance among adolescents experiencing NLEs, timely assessments of IU and tailored interventions to enhance uncertainty tolerance are necessary.

ILT2 and ILT4 Drive Myeloid Suppression via Both Overlapping and Distinct Mechanisms.

Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune-suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contribution of ILT2 and ILT4 to immune inhibition in the context of solid tumor tissue has not been fully explored. We present evidence that both ILT2 and ILT4 contribute to myeloid inhibition. We found that although ILT2 inhibits myeloid cell activation in the context of trans-engagement by MHC-I, ILT4 efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement. In a 3D spheroid tumor model, dual ILT2/ILT4 blockade was required for the optimal activation of myeloid cells, including the secretion of CXCL9 and CCL5, upregulation of CD86 on dendritic cells, and downregulation of CD163 on macrophages. Humanized mouse tumor models showed increased immune activation and cytolytic T-cell activity with combined ILT2 and ILT4 blockade, including evidence of the generation of immune niches, which have been shown to correlate with clinical response to immune-checkpoint blockade. In a human tumor explant histoculture system, dual ILT2/ILT4 blockade increased CXCL9 secretion, downregulated CD163 expression, and increased the expression of M1 macrophage, IFNγ, and cytolytic T-cell gene signatures. Thus, we have revealed distinct contributions of ILT2 and ILT4 to myeloid cell biology and provide proof-of-concept data supporting the combined blockade of ILT2 and ILT4 to therapeutically induce optimal myeloid cell reprogramming in the tumor microenvironment.

Analysis of Clinical Characteristics and Influencing Factors of Early Neurological Deterioration in Patients With Mild Stroke by Intravenous Alteplase Therapy.

OBJECTIVES: Thrombolysis treatment for patients with mild stroke is controversial. The aim of our study was to investigate the clinical characteristics and influencing factors of early neurological deterioration (END) in this group of patients. METHODS: A retrospective analysis was performed on ischemic stroke patients with intravenous thrombolysis (IVT) in Wenzhou Central Hospital. Subgroup analyses were performed for the mild stroke group and nonmild stroke group, END group, and non-early neurological deterioration group in mild stroke patients, respectively. RESULTS: A total of 498 patients were included in this study. Compared with the control group, the mild stroke group was younger age, less atrial fibrillation, previous history of stroke and less use of antithrombotic drugs, more dyslipidemia, smoking, and drinking. Small artery occlusion type was more common in mild stroke, cardioembolism and stroke of undetermined etiology type were less. In the mild stroke group, the symptomatic intracerebral hemorrhage (sICH) rate was 2.54%, and the END rate was 16.1%. Predictors of END included systolic blood pressure, blood glucose, cardioembolism subtype, sICH, and large vessel occlusion. In END patients, the sICH rate was 10.53%, and 84.21% of cases started to worsen within 12 hours after IVT. There was no statistically significant difference in the time to exacerbation among different subtypes. CONCLUSIONS: The occurrence of mild stroke in young patients was largely related to unhealthy lifestyles. The incidence of END in mild stroke IVT patients was low, with most occurring within 12 hours of IVT. There were many risk factors for END: large vessel occlusion and hyperglycemia were independent risk factors for END after IVT. sICH was an important but rare risk factor for END.

Bioinspired electrically stable, optically tunable thermal management electronic skin via interfacial self-assembly.

The skin is the largest organ in the human body and serves vital functions such as sensation, thermal management, and protection. While electronic skin (E-skin) has made significant progress in sensory functions, achieving adaptive thermal management akin to human skin has remained a challenge. Drawing inspiration from squid skin, we have developed a hybrid electronic-photonic skin (hEP-skin) using an elastomer semi-embedded with aligned silver nanowires through interfacial self-assembly. With mechanically adjustable optical properties, the hEP-skin demonstrates adaptive thermal management abilities, warming in the range of +3.5°C for heat preservation and cooling in the range of -4.2°C for passive cooling. Furthermore, it exhibits an ultra-stable high electrical conductivity of âˆ¼4.5×104 S/cm, even under stretching, bending or torsional deformations over 10,000 cycles. As a proof of demonstration, the hEP-skin successfully integrates stretchable light-emitting electronic skin with adaptive thermal management photonic skin.

A novel self-assembled nanoplatform based on retrofitting poloxamer 188 for triple-negative breast cancer targeting treatment.

Poloxamer 188 is a widely used pharmaceutical excipient, which can be found in a variety of drug formulations. In this study, a novel self-assembled nanoplatform was developed for active targeting of folate receptor-overexpressing triple-negative breast cancer. This platform, FPP NPs, was prepared by the retrofitted poloxamer 188 derivatives, resulting in nanoparticles with an appropriate size (< 100 nm), good stability, and satisfactory biocompatibility. Cellular uptake and in vivo distribution studies showed that the FPP NPs had strong tumor cell uptake and active targeting capabilities. Furthermore, docetaxel (DTX) was loaded into FPP NPs in this research. The resulting DTX/FPP NPs exhibited high drug encapsulation efficiency and drug loading capacity, and could rapidly release DTX under slightly acidic conditions, significantly increasing the antitumor activity of the encapsulated drug both in vitro and in vivo. In addition, DTX/FPP NPs could significantly decrease the hepatotoxicity and nephrotoxicity of DTX. Therefore, this drug delivery nanoplatform, based on retrofitted poloxamer 188 with self-assembly properties in aqueous solution and active targeting capabilities to tumors, may provide a promising approach for targeted treatment of triple-negative breast cancer.

Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression.

Immune checkpoint blockade (ICB) has revolutionized cancer therapy but has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. We demonstrate that NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the NLRP3 inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Loss of NR0B2 increased mammary tumor growth and metastasis. Small molecule agonists, including one developed here, reduced Treg expansion, reduced metastatic growth and improved the efficacy of ICB. This work identifies NR0B2 as a target to re-educate myeloid immune cells providing proof-of-principle that this cholesterol-homeostasis axis may have utility in enhancing ICB.

A wearable electrochemical fabric for cytokine monitoring.

Wearable biosensors monitoring various biomarkers in sweat provide comprehensive and prompt profiling of health states at molecular levels. Cytokines existed in sweat with trace amounts play an important role in cellular activity modulation. Unfortunately, flexible and wearable biosensors for cytokine monitoring have not yet been achieved due to the limitation of membrane-based structure and sensing strategy. Herein, we develop a novel electrochemical fabric based on aptamer-functionalized carbon nanotube/graphene fibers for real-time and in situ monitoring of IL-6, a paramount cytokine biomarker for inflammation and cancer. This fabric system possesses flexibility, anti-fatigue ability and breathability for wearable applications and can apply to different body parts in various forms. Moreover, the electrochemical fabric can track other biomarkers by replacing the coupling aptamer, serving as a universal platform for sweat analysis. This fabric-based platform holds the potential to facilitate an intelligent and personalized health monitoring approach.

Low-Temperature Chemical Bath Deposition of Conformal and Compact NiOX for Scalable and Efficient Perovskite Solar Modules.

A scalable and low-cost deposition of high-quality charge transport layers and photoactive perovskite layers are the grand challenges for large-area and efficient perovskite solar modules and tandem cells. An inverted structure with an inorganic hole transport layer is expected for long-term stability. Among various hole transport materials, nickel oxide has been investigated for highly efficient and stable perovskite solar cells. However, the reported deposition methods are either difficult for large-scale conformal deposition or require a high vacuum process. Chemical bath deposition is supposed to realize a uniform, conformal, and scalable coating by a solution process. However, the conventional chemical bath deposition requires a high annealing temperature of over 400 °C. In this work, an amino-alcohol ligand-based controllable release and deposition of NiOX using chemical bath deposition with a low calcining temperature of 270 °C is developed. The uniform and conformal in-situ growth precursive films can be adjusted by tuning the ligand structure. The inverted structured perovskite solar cells and large-area solar modules reached a champion PCE of 22.03% and 19.03%, respectively. This study paves an efficient, low-temperature, and scalable chemical bath deposition route for large-area NiOX thin films for the scalable fabrication of highly efficient perovskite solar modules.

Association of long-term time in target range for systolic blood pressure with cardiovascular risk in the elderly: a Chinese veteran cohort study.

AIMS: Short-term blood pressure (BP) time in target range (TTR) independently predicts cardiovascular (CV) outcomes in adults. However, there are limited data regarding long-term TTR for BP among elderly participants. We aimed to determine whether future CV risk varies for those who can maintain a long-term systolic BP (SBP) target range by assessing TTR in elderly individuals with hypertension. METHODS AND RESULTS: The Chinese veteran cohort study included 943 elderly participants with hypertension aged over 75 years. The primary outcome was the first occurrence of CV events during annual visits. Time in target range was estimated over 15 years of follow-up using linear interpolation. The target range was defined as 120-140 mmHg according to guidelines. The association between SBP TTR and CV outcomes was estimated using multivariable Cox proportional hazards models. During the 15 year follow-up, the probability of CV events gradually decreased with increasing TTR for SBP. After multivariable adjustment for traditional CV risk factors and mean BP, comparing the highest vs. lowest quartiles of TTR for SBP, the hazard ratios (HRs) [95% confidence intervals (CIs)] were 0.424 (0.289-0.624) for the primary outcome. For each 1 SD increase in TTR, the risk of the primary outcome decreased by 25.4% (HR: 0.746; 95% CI: 0.666-0.834). Consistent findings were observed in sensitivity analyses. CONCLUSION: Greater long-term TTR for SBP was associated with a decreased risk of CV events in elderly individuals independent of mean BP, suggesting that SBP TTR might serve as a modifiable risk factor for future CV health in elderly patients with hypertension. LAY SUMMARY: This ongoing Chinese veteran cohort study adds to the understanding of the relationship between higher long-term systolic blood pressure (SBP) time in target range (TTR) and cardiovascular benefits among elderly individuals with hypertension.

Higher long-term systolic blood pressure (SBP) time in target range (TTR) is associated with a significantly decreased risk of cardiovascular events independent of mean SBP, suggesting that TTR might serve as an essential measure for monitoring BP status. It might be helpful for lowering the risk of cardiovascular events when the time in SBP target range is maintained after antihypertensive therapy.

Alternative splicing of PSMD13 mediated by genetic variants is significantly associated with endometrial cancer risk.

OBJECTIVE: Accumulating evidence has shown that aberrant alternative splicing events are closely associated with the onset and development of cancer. However, whether genetic variants-associated alternative splicing is linked to risk of endometrial cancer remains largely uncertain. METHODS: We identified single nucleotide polymorphisms (SNPs) locates in the splicing number trait locus (sQTL) of endometrial cancer using the CancerSplicing QTL database. In parallel with bioinformatics analysis, we conducted a case-control study comprising 2,000 cases and 2,013 controls to assess the association between identified SNP which possesses mRNA splicing function and endometrial cancer susceptibility. Furthermore, we used the Kaplan-Meier Plotter, The Human Protein Atlas, SPNR, and Spliceman2 databases for sQTL and differential gene expression analyses to identify the genetic variant which most potentially influence the risk of endometrial cancer through alternative splicing to reveal the potential mechanism by which candidate SNPs regulate the risk of endometrial cancer. RESULTS: The results indicated that SNP rs7128029 A

Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/Cyclin B2 pathway.

INTRODUCTION: Extracellular vesicles (EVs)-mediated cell-to-cell communication is crucial for hypoxia-induced cell proliferation and tissue repair, but its function in endogenous cardiac regeneration is still unknown. OBJECTIVES: Herein, we aimed to determine whether hypoxia-inducible circWhsc1 in endothelial EVs promoted cardiomyocyte (CM) proliferation and cardiac regeneration. METHODS: RNA-sequence data was used to identify EV circRNAs that were involved into endogenous cardiac regeneration. Quantitative polymerase chain reactions were conducted to determine circRNA expression in tissue, cells and EVs. Gain- and loss-of-function assays were performed to explore the function of EV-derived circWhsc1 during cardiac regeneration. Western blotting and RNA pulldown assays were used to investigate its underlying mechanism. RESULTS: We found that circWhsc1 was enriched in neonatal mouse hearts, particularly in cardiac ECs, and was further upregulated both in ECs and EC-derived EVs under hypoxic conditions. When cocultured with hypoxia-preconditioned neonatal ECs or their secreted EVs, both neonatal and adult CMs exhibited an increased proliferation rate and G2/M ratio, which could be attenuated by knockdown of circWhsc1 in ECs. In vivo, EC-restricted overexpression of circWhsc1 and EV-mediated delivery of circWhsc1 induced CM proliferation, alleviated cardiac fibrosis and restored cardiac function following myocardial infarction in adult mice. Mechanistic studies revealed that EV-derived circWhsc1 activated TRIM59 by enhancing its phosphorylation, thereby reinforcing the binding of TRIM59 to STAT3, phosphorylating STAT3 and inducing CM proliferation. CONCLUSION: The current study demonstrated that hypoxia-inducible circWhsc1 in EC-derived EVs induces CM proliferation and heart regeneration. EC-CM communication mediated by EV-derived circWhsc1 might represent a prospective therapeutic target for inducing cardiac repair post-myocardial infarction.