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Abstract The Hoek–Brown (H–B) criterion has found widespread application in numerous rock engineering projects. However, its efficacy is compromised by an underestimation of rock strength due to its neglect of the influence of the intermediate principal stress ( $$\sigma_{2}$$ σ 2 ). Experimental evidence underscores the significant impact of $$\sigma_{2}$$ σ 2 . Consequently, there exists an imperative to formulate a three-dimensional (3D) criterion. In this study, a new deviatoric function with two additional parameters ( $$k$$ k and $$A$$ A ) is developed firstly, which ensure compliance with the prerequisites of smoothness and convexity. In addition, the parameters $$k$$ k and $$A$$ A are bonded with the weakening effect of the Lode angle ( $$\theta_{\sigma }$$ θ σ ) and the strengthening effect of the mean stress ( $$\sigma_{m}$$ σ m ), respectively. Then a new 3D strength criterion for rocks is proposed by combining this new deviatoric function and the triaxial compression meridian function of the original H–B criterion. Four distinct sets of test data encompassing various rock types are employed to validate the proposed criterion. The results demonstrate that the proposed criterion adeptly captures the strength characteristics of the four rock types, providing a good depiction of failure surfaces within the 3D principal stress space. Comparative analyses involve the utilization of several existing 3D H–B criteria for strength predictions. The proposed criterion exhibits superior fitting performance for all the selected rocks.

Based on the geochemical parameters and analytical data, the heat conservation equation, mass balance law, Rayleigh fractionation model and other methods were used to quantify the in-situ yield and external flux of crust-derived helium, and the initial He concentration and thermal driving mechanism of mantle-derived helium, in the Ledong Diapir area, the Yinggehai Basin, in order to understand the genetic source, migration and accumulation mechanisms of helium under deep thermal fluid activities. The average content of mantle-derived He is only 0.001 4%, the 3He/4He value is (0.002–2.190)×10−6, and the R/Ra value ranges from 0.01 to 1.52, indicating the contribution of mantle-derived He is 0.09%–19.84%, while the proportion of crust-derived helium can reach over 80%. Quantitative analysis indicates that the crust-derived helium is dominated by external input, followed by in-situ production, in the Ledong diapir area. The crust- derived helium exhibits an in-situ 4He yield rate of (7.66– 7.95)×10−13 cm3/(a·g), an in-situ 4He yield of (4.10–4.25)× 10−4 cm3/g, and an external 4He influx of (5.84–9.06)×10−2 cm3/g. These results may be related to atmospheric recharge into formation fluid and deep rock-water interactions. The ratio of initial mole volume of 3He to enthalpy (W) is (0.004–0.018) ×10−11 cm3/J, and the heat contribution from the deep mantle (XM) accounts for 7.63%–36.18%, indicating that deep hot fluid activities drive the migration of mantle-derived 3He. The primary helium migration depends on advection, while the secondary migration is controlled by hydrothermal degassing and gas-liquid separation. From deep to shallow layers, the CO2/3He value rises from 1.34×109 to 486×109, indicating large amount of CO2 has escaped. Under the influence of deep thermal fluid, helium migration and accumulation mechanisms include: deep heat driven diffusion, advection release, vertical hydrothermal degassing, shallow lateral migration, accumulation in traps far from faults, partial pressure balance and sealing capability.

Abstract Pulmonary arterial hypertension (PAH) is associated with aberrant pulmonary vascular smooth muscle cell (PASMC) function and vascular remodeling. MiR‐30d plays an important role in the pathogenesis of several cardiovascular disorders. However, the function of miR‐30d in PAH progression remained unknown. Our study shows that circulating miR‐30d level is significantly reduced in the plasma from PAH patients. In miR‐30d transgenic (TG) rats, overexpressing miR‐30d attenuates monocrotaline (MCT)‐induced pulmonary hypertension (PH) and pulmonary vascular remodeling. Increasing miR‐30d also inhibits platelet‐derived growth factor‐bb (PDGF‐bb)‐induced proliferation and migration of human PASMC. Metadherin (MTDH) and phosphodiesterase 5A (PDE5A) are identified as direct target genes of miR‐30d. Meanwhile, nuclear respiratory factor 1 (NRF1) acts as a positive upstream regulator of miR‐30d. Using miR‐30d knockout (KO) rats treated with sildenafil, a PDE5A inhibitor that is used in clinical PAH therapies, it is further found that suppressing miR‐30d partially attenuates the beneficial effect of sildenafil against MCT‐induced PH and vascular remodeling. The present study shows a protective effect of miR‐30d against PAH and pulmonary vascular remodeling through targeting MTDH and PDE5A and reveals that miR‐30d modulates the beneficial effect of sildenafil in treating PAH. MiR‐30d should be a prospective target to treat PAH and pulmonary vascular remodeling.

RNA N6-methyladenosine (m6A) methylation is the most abundant and conserved RNA modification in eukaryotes. It participates in the regulation of RNA metabolism and various pathophysiological processes. Non-coding RNAs (ncRNAs) are defined as small or long transcripts which do not encode proteins and display numerous biological regulatory functions. Similar to mRNAs, m6A deposition is observed in ncRNAs. Studying RNA m6A modifications on ncRNAs is of great importance specifically to deepen our understanding of their biological roles and clinical implications. In this review, we summarized the recent research findings regarding the mutual regulation between RNA m6A modification and ncRNAs (with a specific focus on microRNAs, long non-coding RNAs, and circular RNAs) and their functions. We also discussed the challenges of m6A-containing ncRNAs and RNA m6A as therapeutic targets in human diseases and their future perspective in translational roles.

Deep rocks are typically under a true-triaxial stress state. The strength of deep rock is thus dictated by both the direction and magnitude of principal stresses. The formulation of three-dimensional strength criterion for rocks is thus essential for evaluating the stability of deep-buried rock structures. With advancements in true-triaxial experimental instrumentation, several three-dimensional strength criteria have been proposed, necessitating a systematic review and consolidation of these criteria. This review first introduces the concept of three-dimensional stress state. Subsequently, classical strength criteria such as the Mohr-Coulomb Criterion, the Hoek-Brown criterion, and the Drucker-Prager criterion are reiterated. However, these traditional strength criteria inadequately describe rock strength under true-triaxial stress conditions. To better capture the influence of intermediate principal stress, hydrostatic pressure, and Lode angle on rock strength, researchers have revised classical strength criteria. Modified strength criteria and unified strength criteria based on classical formulations are also introduced. Notably, the unified strength criterion incorporates multiple single criteria and demonstrates wider applicability. Furthermore, beyond macroscopic strength criteria, this review also discusses micromechanical strength criteria, where the stress state and crack propagation govern rock mechanical behaviors. This comprehensive review may serve as a valuable source for addressing the problem of deep rock strength in energy extraction and other rock engineering applications.

This is an essay in the field of mining engineering, which summarized the current situation and characteristics of tungsten tailings resources, and expounds the urgency and necessity of comprehensive utilization of tungsten tailings resources under the requirements of current economic development and environmental protection. The research status of recovery of valuable metal and valuable non-metals in tungsten tailings was comprehensively evaluated. The application and application prospects of tungsten tailings in new building materials were introduced in detail. Combined with the current research focus on tungsten tailings resources in China, the development direction of comprehensive utilization of tungsten tailings is proposed.

Exercise can stimulate physiological cardiac growth and provide cardioprotection effect in ischemia/reperfusion (I/R) injury. MiR-210 is regulated in the adaptation process induced by exercise; however, its impact on exercise-induced physiological cardiac growth and its contribution to exercise-driven cardioprotection remain unclear. We investigated the role and mechanism of miR-210 in exercise-induced physiological cardiac growth and explored whether miR-210 contributes to exercise-induced protection in alleviating I/R injury. Here, we first observed that regular swimming exercise can markedly increase miR-210 levels in the heart and blood samples of rats and mice. Circulating miR-210 levels were also elevated after a programmed cardiac rehabilitation in patients that were diagnosed of coronary heart diseases. In 8-week swimming model in wild-type (WT) and miR-210 knockout (KO) rats, we demonstrated that miR-210 was not integral for exercise-induced cardiac hypertrophy but it did influence cardiomyocyte proliferative activity. In neonatal rat cardiomyocytes, miR-210 promoted cell proliferation and suppressed apoptosis while not altering cell size. Additionally, miR-210 promoted cardiomyocyte proliferation and survival in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and AC16 cell line, indicating its functional roles in human cardiomyocytes. We further identified miR-210 target genes, cyclin-dependent kinase 10 (CDK10) and ephrin-A3 (EFNA3), that regulate cardiomyocyte proliferation and apoptosis. Finally, miR-210 KO and WT rats were subjected to swimming exercise followed by I/R injury. We demonstrated that miR-210 crucially contributed to exercise-driven cardioprotection against I/R injury. In summary, this study elucidates the role of miR-210, an exercise-responsive miRNA, in promoting the proliferative activity of cardiomyocytes during physiological cardiac growth. Furthermore, miR-210 plays an essential role in mediating the protective effects of exercise against cardiac I/R injury. Our findings suggest exercise as a potent nonpharmaceutical intervention for inducing miR-210, which can alleviate I/R injury and promote cardioprotection.

Abstract Exercise has well-recognized beneficial effects on the whole body. Previous studies suggest that exercise could promote tissue regeneration and repair in various organs. In this review, we have summarized the major effects of exercise on tissue regeneration primarily mediated by stem cells and progenitor cells in skeletal muscle, nervous system, and vascular system. The protective function of exercise-induced stem cell activation under pathological conditions and aging in different organs have also been discussed in detail. Moreover, we have described the primary molecular mechanisms involved in exercise-induced tissue regeneration, including the roles of growth factors, signaling pathways, oxidative stress, metabolic factors, and non-coding RNAs. We have also summarized therapeutic approaches that target crucial signaling pathways and molecules responsible for exercise-induced tissue regeneration, such as IGF1, PI3K, and microRNAs. Collectively, the comprehensive understanding of exercise-induced tissue regeneration will facilitate the discovery of novel drug targets and therapeutic strategies.

Muscle atrophy is debilitating and can be induced by several stressors. Unfortunately, there are no effective pharmacological treatment until now. MicroRNA (miR)-29b is an important target that we identified to be commonly involved in multiple types of muscle atrophy. Although sequence-specific inhibition of miR-29b has been developed, in this study, we report a novel small-molecule miR-29b inhibitor that targets miR-29b hairpin precursor (pre-miR-29b) (Targapremir-29b-066 [TGP-29b-066]) considering both its three-dimensional structure and the thermodynamics of interaction between pre-miR-29b and the small molecule. This novel small-molecule inhibitor has been demonstrated to attenuate muscle atrophy induced by angiotensin II (Ang II), dexamethasone (Dex), and tumor necrosis factor α (TNF-α) in C2C12 myotubes, as evidenced by increase in the diameter of myotube and decrease in the expression of Atrogin-1 and MuRF-1. Moreover, it can also attenuate Ang II-induced muscle atrophy in mice, as evidenced by a similar increase in the diameter of myotube, reduced Atrogin-1 and MuRF-1 expression, AKT-FOXO3A-mTOR signaling activation, and decreased apoptosis and autophagy. In summary, we experimentally identified and demonstrated a novel small-molecule inhibitor of miR-29b that could act as a potential therapeutic agent for muscle atrophy.

Abstract Neonatal mouse heart can regenerate after left ventricle (LV) apical resection (AR). Since current AR rodent method is accomplished by resecting LV apex until exposure of LV chamber, it is relatively difficult to operate reproducibly. We aimed to develop a modified AR method with high accuracy and reproducibility and to investigate whether cardiac regenerative capacity could be replicated in neonatal rats. For 15% AR of whole heart weight in 1-day-old (P1) neonatal mice, a modified 10 μL pipette tip cut to 0.48 mm in internal diameter was connected to a vacuum pump working at 0.06 ± 0.005 MPa and gently kept in touch with LV apex for nearly but no more than 12 s. LV apex was resected by a single incision adjacent to the pipette tip. The modified AR method in P1 mice achieved cardiac structural and functional recovery at 21 days post resection (dpr). Data from different operators showed smaller variation of resected LV apex and higher reproducibility using the modified AR method. Furthermore, we showed that 5% AR of whole heart weight in P1 neonatal rats using a modified 200 μL pipette tip cut to 0.63 mm in internal diameter led to complete regeneration of LV apex and full preservation of cardiac function at 42 dpr. In conclusion, the modified AR rodent model leads to accurate resection of LV apex with high homogeneity and reproducibility and it is practically convenient for the study of structural, functional, and molecular mechanisms of cardiac regeneration in both neonatal mice and rats.

Abstract Background Age‐associated sarcopenia is characterized of progressed loss of skeletal muscle power, mass, and function, which affects human physical activity and life quality. Besides, accompanied with sarcopenia, aged population also faces a series of metabolic dysfunctions. Irisin, the cleaved form of fibronectin type III domain‐containing protein 5 (FNDC5), is a myokine induced by exercise and has been shown to exert multiple beneficial effects on health. The goal of the study is to investigate the alterations of Fndc5/irisin in skeletal muscles during ageing and whether irisin administration could ameliorate age‐associated sarcopenia and metabolic dysfunction. Methods The mRNA and protein levels of FNDC5/irisin in skeletal muscle and serum from 2‐ and 24‐month‐old mice or human subjects were analysed using qRT‐PCR and western blot. FNDC5/irisin knockout mice were generated to investigate the consequences of FNDC5/irisin deletion on skeletal muscle mass, as well as morphological and molecular changes in muscle during ageing via histological and molecular analysis. To identify the therapeutic effects of chronic irisin treatment in mice during ageing, in vivo intraperitoneal administration of 2 mg/kg recombinant irisin was performed three times per week in ageing mice (14‐month‐old) for 4 months or in aged mice (22‐month‐old) for 1 month to systematically investigate irisin's effects on age‐associated sarcopenia and metabolic performances, including grip strength, body weights, body composition, insulin sensitivity, energy expenditure, serum parameters and phenotypical and molecular changes in fat and liver. Results We showed that the expression levels of irisin, as well as its precursor Fndc5, were reduced at mRNA and protein expression levels in muscle during ageing. In addition, via phenotypic analysis of FNDC5/irisin knockout mice, we found that FNDC5/irisin deficiency in aged mice exhibited aggravated muscle atrophy including smaller grip strength (−3.23%, P

Exercise is a vital component in maintaining optimal health and serves as a prospective therapeutic intervention for various diseases. The human microbiome, comprised of trillions of microorganisms, plays a crucial role in overall health. Given the advancements in microbiome research, substantial databases have been created to decipher the functionality and mechanisms of the microbiome in health and disease contexts. This review presents an initial overview of microbiomics development and related databases, followed by an in-depth description of the multi-omics technologies for microbiome. It subsequently synthesizes the research pertaining to exercise-induced modifications of the microbiome and diseases that impact the microbiome. Finally, it highlights the potential therapeutic implications of an exercise-modulated microbiome in intestinal disease, obesity and diabetes, cardiovascular disease, and immune/inflammation-related diseases.

Exercise has long been known for its active role in improving physical fitness and sustaining health. Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases. It is well-documented that exercise maintains and restores homeostasis at the organismal, tissue, cellular, and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions. Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health, including the integrity of barriers, containment of local perturbations, recycling and turnover, integration of circuitries, rhythmic oscillations, homeostatic resilience, hormetic regulation, as well as repair and regeneration. Furthermore, we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise. This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions. We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.

Background: Exercise is beneficial for muscle atrophy. Peroxisome proliferator-activated receptor gamma (PPARγ) and microRNA-29b (miR-29b) have been reported to be responsible for angiotensinⅡ (AngⅡ)-induced muscle atrophy. However, it is unclear whether exercise can protect AngⅡ-induced muscle atrophy by targeting PPARγ/miR-29b. Methods: Skeletal muscle atrophy in both the control group and the run group was established by AngⅡ infusion; after 1 week of exercise training, the mice were sacrificed, and muscle weight was determined. Myofiber size was measured by hematoxylin-eosin and wheat-germ agglutinin staining. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The expression level of muscle atrogenes, including F-box only protein 32 (FBXO32, also called Atrogin-1) and muscle-specific RING-finger 1 (MuRF-1), the phosphorylation level of protein kinase B (PKB, also called AKT)/forkhead box O3A (FOXO3A)/mammalian target of rapamycin (mTOR) pathway proteins, the expression level of PPARγ and apoptosis-related proteins, including B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), cysteine-aspartic acid protease 3 (caspase-3), and cleaved-caspase-3, were determined by western blot. The expression level of miR-29b was checked by reverse-transcription quantitative polymerase chain reaction. A PPARγ inhibitor (T0070907) or adeno-associated virus serotype-8 (AAV8)-mediated miR-29b overexpression was used to demonstrate whether PPARγ activation or miR-29b inhibition mediates the beneficial effects of exercise in AngⅡ-induced muscle atrophy. Results: Exercise can significantly attenuate AngⅡ-induced muscle atrophy, which is demonstrated by increased skeletal muscle weight, cross-sectional area of myofiber, and activation of AKT/mTOR signaling and by decreased atrogenes expressions and apoptosis. In AngⅡ-induced muscle atrophy mice models, PPARγ was elevated whereas miR-29b was decreased by exercise. The protective effects of exercise in AngⅡ-induced muscle atrophy were inhibited by a PPARγ inhibitor (T0070907) or adeno-associated virus serotype-8 (AAV8)-mediated miR-29b overexpression. Conclusion: Exercise attenuates AngⅡ-induced muscle atrophy by activation of PPARγ and suppression of miR-29b.

The benefit of regular exercise on the heart has been well documented but the role of RNA m6A modification in exercise-induced cardiac remodelling remains largely unknown. In this study, the authors report that METTL14 plays an important role in RNA m6A modification in exercise-induced physiological cardiac hypertrophy.

Abstract Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases (CVD). Functional and mechanistic studies that employ animal exercise models as well as observational and interventional cohort studies with human participants, have contributed considerably in delineating the essential signaling pathways by which exercise promotes cardiovascular fitness and health. First, this review summarizes the beneficial impact of exercise on multiple aspects of cardiovascular health. We then discuss in detail the signaling pathways mediating exercise’s benefits for cardiovascular health. The exercise-regulated signaling cascades have been shown to confer myocardial protection and drive systemic adaptations. The signaling molecules that are necessary for exercise-induced physiological cardiac hypertrophy have the potential to attenuate myocardial injury and reverse cardiac remodeling. Exercise-regulated noncoding RNAs and their associated signaling pathways are also discussed in detail for their roles and mechanisms in exercise-induced cardioprotective effects. Moreover, we address the exercise-mediated signaling pathways and molecules that can serve as potential therapeutic targets ranging from pharmacological approaches to gene therapies in CVD. We also discuss multiple factors that influence exercise’s effect and highlight the importance and need for further investigations regarding the exercise-regulated molecules as therapeutic targets and biomarkers for CVD as well as the cross talk between the heart and other tissues or organs during exercise. We conclude that a deep understanding of the signaling pathways involved in exercise’s benefits for cardiovascular health will undoubtedly contribute to the identification and development of novel therapeutic targets and strategies for CVD.

Atherosclerosis, formed by fibrofatty lesions in the artery wall, underpins myocardial infarctions, strokes and disabling peripheral artery diseases. Inflammation with multiple maladaptive roles runs through atherosclerotic inception, propagation, and complications. Given degree of inflammation differing among atherosclerotics, inflammation-targeted nanomedicine may produce individualized monitoring and manipulation of inflammatory regulators beyond traditionally slowing down atherosclerosis progression. Equipped with biomimetic membrane, microenvironment-responsive and targeting structures, nanomedicines could escape from the innate immune system and autonomously navigate to targeted lesions, thereby muting inflammation in atherosclerotic sites. Moreover, nanoparticles’ advantages go beyond advancing pharmacology. The optimal physicochemical properties of nanoparticles favor noninvasive imaging function to provide diagnostic and prognostic information of atherosclerotic plaques. Despite efficacious ability of the preclinical anti-inflammation nanotherapeutics to reduce atherosclerotic risks, future translation of inflammation-targeted nanomedicines requires to comprehensively refine the strategies that the nanomedicines forestall inflammatory pathways via systemic exposure, drug-cell interactions, and endothelial barrier reconstruction. In this review, we outline the development of diverse nanomedicines to specifically identify pathophysiological changes and combat advanced atherosclerosis along with dynamically tracing inflammatory markers. Finally, challenges and opportunities of inflammation-targeted nanomedicines are highlighted to pave avenues toward personalized medicine for atherosclerosis to stem the growing global burden of cardiovascular diseases.

Abstract Inhibition of pathological cardiac hypertrophy is recognized as an important therapeutic strategy for heart failure, although effective targets are still lacking in clinical practice. Homeodomain interacting protein kinase 1 (HIPK1) is a conserved serine/threonine kinase that can respond to different stress signals, however, whether and how HIPK1 regulates myocardial function is not reported. Here, it is observed that HIPK1 is increased during pathological cardiac hypertrophy. Both genetic ablation and gene therapy targeting HIPK1 are protective against pathological hypertrophy and heart failure in vivo. Hypertrophic stress‐induced HIPK1 is present in the nucleus of cardiomyocytes, while HIPK1 inhibition prevents phenylephrine‐induced cardiomyocyte hypertrophy through inhibiting cAMP‐response element binding protein (CREB) phosphorylation at Ser271 and inactivating CCAAT/enhancer‐binding protein β (C/EBPβ)‐mediated transcription of pathological response genes. Inhibition of HIPK1 and CREB forms a synergistic pathway in preventing pathological cardiac hypertrophy. In conclusion, HIPK1 inhibition may serve as a promising novel therapeutic strategy to attenuate pathological cardiac hypertrophy and heart failure.

Abstract Circulating circular RNAs (circRNAs) are emerging as novel biomarkers for cardiovascular diseases (CVDs). Machine learning can provide optimal predictions on the diagnosis of diseases. Here we performed a proof‐of‐concept study to determine if combining circRNAs with an artificial intelligence approach works in diagnosing CVD. We used acute myocardial infarction (AMI) as a model setup to prove the claim. We determined the expression level of five hypoxia‐induced circRNAs, including cZNF292, cAFF1, cDENND4C, cTHSD1, and cSRSF4, in the whole blood of coronary angiography positive AMI and negative non‐AMI patients. Based on feature selection by using lasso with 10‐fold cross validation, prediction model by logistic regression, and ROC curve analysis, we found that cZNF292 combined with clinical information (CM), including age, gender, body mass index, heart rate, and diastolic blood pressure, can predict AMI effectively. In a validation cohort, CM + cZNF292 can separate AMI and non‐AMI patients, unstable angina and AMI patients, acute coronary syndromes (ACS), and non‐ACS patients. RNA stability study demonstrated that cZNF292 was stable. Knockdown of cZNF292 in endothelial cells or cardiomyocytes showed anti‐apoptosis effects in oxygen glucose deprivation/reoxygenation. Thus, we identify circulating cZNF292 as a potential biomarker for AMI and construct a prediction model “CM + cZNF292.”

Abstract Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA‐binding protein 43 (TDP‐43) and promotes aggregation of TDP‐43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP‐AMP synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1‐339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro‐atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.

Background: Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart. Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes. However, it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth. We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth. Methods: Adult C57BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth. Oral treatment with vascular endothelial growth factor receptor 3 (VEGFR3) inhibitor SAR131675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation. Furthermore, human dermal lymphatic endothelial cell (LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy. Results: Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1–positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels. VEGFR3 was upregulated in the exercised heart, while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes, which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise. Furthermore, LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulin-like growth factor-1 and the extracellular protein Reelin, while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects. Functional rescue assays further demonstrated that protein kinase B (AKT) activation, as well as reduced CCAAT enhancer-binding protein beta (C/EBPβ) and increased CBP/p300-interacting transactivators with E (glutamic acid)/D (aspartic acid)–rich-carboxylterminal domain 4 (CITED4), contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation. Conclusion: Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation, and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis. These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth.

Abstract Muscle atrophy is a frequently observed complication, characterized by the loss of muscle mass and strength, which diminishes the quality of life and survival. No effective therapy except exercise is currently available. In our previous study, repressing miR-29b has been shown to reduce muscle atrophy. In our current study, we have constructed artificially engineered extracellular vesicles for the delivery of CRISPR/Cas9 to target miR-29b (EVs-Cas9-29b). EVs-Cas9-29b has shown a favorable functional effect with respect to miR-29b repression in a specific and rapid manner by gene editing. In in vitro conditions, EVs-Cas9-29b could protect against muscle atrophy induced by dexamethasone (Dex), angiotensin II (AngII), and tumor necrosis factor-alpha (TNF-α). And EVs-Cas9-29b introduced in vivo preserved muscle function in the well-established immobilization and denervation-induced muscle atrophy mice model. Our work demonstrates an engineered extracellular vesicles delivery of the miR-29b editing system, which could be potentially used for muscle atrophy therapy.

Abstract Commonly used prediction models have been primarily constructed without taking physical activity into account. Using the Kailuan physical activity cohorts from Asymptomatic Polyvascular Abnormalities in Community (APAC) study, we developed a 9‐year cardiovascular or cerebrovascular disease (CVD) risk prediction equation. Participants in this study were included from APAC cohort, which included 5440 participants from the Kailuan cohort in China. Cox proportional hazard regression model was applied to construct sex‐specific risk prediction equations for the physical activity cohort (PA equation). Proposed equations were compared with the 10‐year risk prediction model, which is developed for atherosclerotic cardiovascular disease risk in Chinese cohorts (China‐PAR equation). C statistics of PA equations were 0.755 (95% confidence interval, 0.750–0.758) for men and 0.801 (95% confidence interval, 0.790–0.813) for women. The estimated area under the receiver operating characteristic curves in the validation set shows that the PA equations perform as good as the China‐PAR. From calibration among four categories of predicted risks, the predicted risk rates by PA equations were almost identical to the Kaplan–Meier observed rates. Therefore, our developed sex‐specific PA equations have effective performance for predicting CVD for physically active cohorts in the physical activity cohort in Kailuan.

Abstract Background Gut microbiota plays important roles in health maintenance and diseases. Physical exercise has been demonstrated to be able to modulate gut microbiota. However, the potential role of gut microbiome in exercise protection to myocardial infarction (MI) remains unclear. Results Here, we discovered exercise training ameliorated cardiac dysfunction and changed gut microbial richness and community structure post-MI. Moreover, gut microbiota pre-depletion abolished the protective effects of exercise training in MI mice. Furthermore, mice receiving microbiota transplants from exercised MI mice had better cardiac function compared to mice receiving microbiota transplants from non-exercised MI mice. Mechanistically, we analyzed metabolomics in fecal samples from exercised mice post-MI and identified 3-Hydroxyphenylacetic acid (3-HPA) and 4-Hydroxybenzoic acid (4-HBA), which could be applied individually to protect cardiac dysfunction post-MI and apoptosis through NRF2. Conclusions Together, our study provides new insights into the role of gut microbiome in exercise protection to MI, offers opportunities to modulate cardiovascular diseases by exercise, microbiome and gut microbiota-derived 3-HPA and 4-HBA. Video Abstract

With the increasing demand for person re-identification (Re-ID) tasks, the need for all-day retrieval has become an inevitable trend. Nevertheless, single-modal Re-ID is no longer sufficient to meet this requirement, making Multi-Modal Data crucial in Re-ID. Consequently, a Visible-Infrared Person Re-Identification (VI Re-ID) task is proposed, which aims to match pairs of person images from the visible and infrared modalities. The significant modality discrepancy between the modalities poses a major challenge. Existing VI Re-ID methods focus on cross-modal feature learning and modal transformation to alleviate the discrepancy but overlook the impact of person contour information. Contours exhibit modality invariance, which is vital for learning effective identity representations and cross-modal matching. In addition, due to the low intra-modal diversity in the visible modality, it is difficult to distinguish the boundaries between some hard samples. To address these issues, we propose the Graph Sampling-based Multi-stream Enhancement Network (GSMEN). Firstly, the Contour Expansion Module (CEM) incorporates the contour information of a person into the original samples, further reducing the modality discrepancy and leading to improved matching stability between image pairs of different modalities. Additionally, to better distinguish cross-modal hard sample pairs during the training process, an innovative Cross-modality Graph Sampler (CGS) is designed for sample selection before training. The CGS calculates the feature distance between samples from different modalities and groups similar samples into the same batch during the training process, effectively exploring the boundary relationships between hard classes in the cross-modal setting. Some experiments conducted on the SYSU-MM01 and RegDB datasets demonstrate the superiority of our proposed method. Specifically, in the VIS→IR task, the experimental results on the RegDB dataset achieve 93.69% for Rank-1 and 92.56% for mAP.

Exercise training (ET) is an important non-drug adjuvant therapy against many human diseases, including cardiovascular diseases. The appropriate ET intensity induces beneficial adaptions and improves physiological function and cardiopulmonary fitness. The mechanisms of exercise-induced cardioprotective effects are still not fully understood. However, mounting evidence suggest that microRNAs (miRNAs) play crucial role in this process and are essential in responding to exercise-stress and mediating exercise-protective effects. Thus, this review summarizes the biogenesis of miRNAs, the mechanism of miRNA action, and specifically the miRNAs involved in exercise-induced cardio-protection used as therapeutic targets for treating cardiovascular diseases.

Cardiovascular disease is one of the leading causes of mortality worldwide. Recent studies have shown that circular RNAs (circRNAs) have emerged as important players in the prevention and treatment of cardiovascular diseases. circRNAs are a class of endogenous noncoding RNAs that are generated by back-splicing and are involved in many pathophysiological processes. In this review, we outline the current research progress on the regulatory roles of circRNAs in cardiovascular diseases. Further, new technologies and methods available for identifying, validating, synthesizing, and analyzing circRNAs, as well as their applications in therapeutics, are highlighted here. Moreover, we summarize the increasing insights into the potential use of circRNAs as circulating diagnostic and prognostic biomarkers. Finally, we discuss the prospects and challenges of circRNA therapeutic applications for cardiovascular disease therapy, with a particular focus on developing circRNA synthesis and engineering delivery systems.

Muscle atrophy is a common complication of many chronic diseases including heart failure, cancer cachexia, aging, etc. Unhealthy habits and usage of hormones such as dexamethasone can also lead to muscle atrophy. However, the underlying mechanisms of muscle atrophy are not completely understood. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in muscle atrophy. This review mainly discusses the regulation of ncRNAs in muscle atrophy induced by various factors such as heart failure, cancer cachexia, aging, chronic obstructive pulmonary disease (COPD), peripheral nerve injury (PNI), chronic kidney disease (CKD), unhealthy habits, and usage of hormones; highlights the findings of ncRNAs as common regulators in multiple types of muscle atrophy; and summarizes current therapies and underlying mechanisms for muscle atrophy. This review will deepen the understanding of skeletal muscle biology and provide new strategies and insights into gene therapy for muscle atrophy.

Growing evidence has demonstrated exercise as an effective way to promote cardiovascular health and protect against cardiovascular diseases However, the underlying mechanisms of the beneficial effects of exercise have yet to be elucidated. Animal exercise studies are widely used to investigate the key mechanisms of exercise-induced cardiovascular protection. However, standardized procedures and well-established evaluation indicators for animal exercise models are needed to guide researchers in carrying out effective, high-quality animal studies using exercise to prevent and treat cardiovascular diseases. In our review, we present the commonly used animal exercise models in cardiovascular research and propose a set of standard procedures for exercise training, emphasizing the appropriate measurements and analysis in these chronic exercise models. We also provide recommendations for optimal design of animal exercise studies in cardiovascular research, including the choice of exercise models, control of exercise protocols, exercise at different stages of disease, and other considerations, such as age, sex, and genetic background. We hope that this position paper will promote basic research on exercise-induced cardiovascular protection and pave the way for successful translation of exercise studies from bench to bedside in the prevention and treatment of cardiovascular diseases.

Summary: Background: Homeodomain-Interacting Protein Kinase 2 (HIPK2) has been reported to maintain basal cardiac function, however, its role in pathological cardiac remodeling remains unclear. Methods: HIPK2 inhibitors (tBID and PKI1H) treated mice and two lines of HIPK2−/− mice were subjected to transverse aortic constriction (TAC). HIPK2 knockdown were performed in neonatal rat cardiomyocytes (NRCMs), neonatal rat cardiac fibroblasts (NRCFs), and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Microarray analysis was used to screen HIPK2 targets. Overexpression of early growth response 3 (EGR3) and C-type lectin receptor 4D (CLEC4D) were performed in NRCMs, while an activator of Smad3 was used in NRCFs, to rescue the effects of HIPK2 knockdown. Finally, the effects of EGR3 and CLEC4D knockdown by AAV9 in TAC were determined. Findings: HIPK2 was elevated in TAC mice model, as well as cardiomyocyte hypertrophy and NRCFs fibrosis model. Pharmacological and genetic inhibition of HIPK2 improved cardiac function and suppressed cardiac hypertrophy and fibrosis induced by TAC. In vitro, HIPK2 inhibition prevented cardiomyocyte hypertrophic growth and NRCFs proliferation and differentiation. At the mechanistic level, we identified EGR3 and CLEC4D as new targets of HIPK2, which were regulated by ERK1/2-CREB and mediated the protective function of HIPK2 inhibition in cardiomyocytes. Meanwhile, inhibition of phosphorylation of Smad3 was responsible for the suppression of cardiac fibroblasts proliferation and differentiation by HIPK2 inhibition. Finally, we found that inhibition of EGR3 or CLEC4D protected against TAC. Interpretation: HIPK2 inhibition protects against pathological cardiac remodeling by reducing EGR3 and CLEC4D with ERK1/2-CREB inhibition in cardiomyocytes, and by suppressing the phosphorylation of Smad3 in cardiac fibroblasts. Funding: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J.X.), National Natural Science Foundation of China (82020108002 and 81911540486 to J.X., 81400647 to MJ Xu), the grant from Science and Technology Commission of Shanghai Municipality (21XD1421300 and 20DZ2255400 to J.X.), the “Dawn” Program of Shanghai Education Commission (19SG34 to J.X.), and Shanghai Sailing Program (21YF1413200 to Q.Z.).

Summary: Background: Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed. Methods: The expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d. Findings: miR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes. Interpretation: Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy. Funding: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the “Dawn” Program of Shanghai Education Commission (19SG34 to J Xiao), the “Chen Guang” project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).

Abstract Cardiovascular diseases (CVDs) are a major cause of mortality worldwide, which are mainly driven by factors such as aging, sedentary lifestyle, and excess alcohol use. Exercise targets several molecules and protects hearts against many of these physiological and pathological stimuli. Accordingly, it is widely recognized as an effective therapeutic strategy for CVD. To investigate the molecular mechanism of exercise in cardiac protection, we identify and describe several crucial targets identified from exercised hearts. These targets include insulin-like growth factor 1 (IGF1)-phosphatidylinositol 3 phosphate kinase (PI3K)/protein kinase B (AKT), transcription factor CCAAT/enhancer-binding protein β (C/EBPβ), cardiac microRNAs (miRNAs, miR-222 and miR-17-3p etc.), exosomal-miRNAs (miR-342, miR-29, etc.), Sirtuin 1 (SIRT1), and nuclear factor erythroid 2‑related factor/metallothioneins (Nrf2/Mts). Targets identified from exercised hearts can alleviate injury via multiple avenues, including: (1) promoting cardiomyocyte proliferation; (2) facilitating cardiomyocyte growth and physiologic hypertrophy; (3) elevating the anti-apoptotic capacity of cardiomyocytes; (4) improving vascular endothelial function; (5) inhibiting pathological remodeling and fibrosis; (6) promoting extracellular vesicles (EVs) production and exosomal-molecules transfer. Exercise is one treatment (‘stone’), which is cardioprotective via multiple avenues (‘birds’), and is considered ‘killing multiple birds with one stone’ in this review. Further, we discuss the potential application of EV cargos in CVD treatment. We provide an outline of targets identified from the exercised heart and their mechanisms, as well as novel ideas for CVD treatment, which may provide novel direction for preclinical trials in cardiac rehabilitation.

The activation of the renin-angiotensin system (RAS) induced by increased angiotensin II (AngII) levels has been implicated in muscle atrophy, which is involved in the pathogenesis of congestive heart failure. Although peroxisome proliferator-activated receptor gamma (PPARγ) activation can suppress RAS, the exact role of PPARγ in AngII-induced muscle atrophy is unclear. Here we identified PPARγ as a negative regulator of miR-29b, a microRNA that is able to promote multiple types of muscle atrophy. Suppression of miR-29b could prevent AngII-induced muscle atrophy both in vitro and in vivo. IGF1, PI3K(p85α), and Yin Yang 1 (YY1) were identified as target genes of miR-29b, and overexpression of these targets could rescue AngII-induced muscle atrophy. Importantly, inhibition of PPARγ was sufficient to induce muscle atrophy, while PPARγ overexpression could attenuate that. These data indicate that the PPARγ/miR-29b axis mediates AngII-induced muscle atrophy, and increasing PPARγ or inhibiting miR-29b represents a promising approach to counteract AngII-induced muscle atrophy.

Extracellular vesicles (EVs) or exosomes are nanosized extracellular particles that contain proteins, DNA, non-coding RNA (ncRNA) and other molecules, which are widely present in biofluids throughout the body. As a key mediator of intercellular communication, EVs transfer their cargoes to target cells and activate signaling transduction. Increasing evidence shows that ncRNA is involved in a variety of pathological and physiological processes through various pathways, particularly the inflammatory response. Macrophage, one of the body’s “gatekeepers”, plays a crucial role in inflammatory reactions. Generally, macrophages can be classified as pro-inflammatory type (M1) or anti-inflammatory type (M2) upon their phenotypes, a phenomenon termed macrophage polarization. Increasing evidence indicates that the polarization of macrophages plays important roles in the progression of cardiovascular diseases (CVD). However, the role of exosomal ncRNA in regulating macrophage polarization and the role of polarized macrophages as an important source of EV in CVD remains to be elucidated. In this review, we summarize the role and molecular mechanisms of exosomal-ncRNA in regulating macrophage polarization during CVD development, focusing on their cellular origins, functional cargo, and their detailed effects on macrophage polarization. We also discuss the role of polarized macrophages and their derived EV in CVD as well as the therapeutic prospects of exosomal ncRNA in the treatment of CVD.

The adoption of the droop control provides a feasible scheme for the distributed generation connected to the utility grid. Nevertheless, it does not contribute to the inertia and damping factor necessary for power systems. In order to achieve increased stability of microgrids, some scholars simulate the operating characteristics of traditional synchronous generators through control equations, thus virtual synchronous generator control (VSG) was developed. Firstly, the small signal models of inverter based on droop control and VSG control are built in grid-connected (GC) state and stand-alone (SA) state to compare the dynamic response when load transition and power reference change. And we can deduce that in terms of dynamic response neither of these two control strategies can simultaneously satisfy the stringent requirements of different modes of operation. Then, by integrating the advantages of the traditional droop control and VSG control, inertial droop control is introduced in this paper. The presented inertial droop control not only features virtual inertia but also adds compensators to the output power part of the active power control loop to ensure the dynamic response of the system. In the GC state, inertial droop control helps to restrain power oscillations, shorten power adjustment time, and minimize frequency fluctuations to maintain frequency stability. In the SA state, the inertial droop control enables to achieve high enough inertia and damping properties. Finally, this paper demonstrates the superiority of the inertial droop control by means of simulation results.

Abstract Air pollution, via ambient PM2.5, is a big threat to public health since it associates with increased hospitalisation, incidence rate and mortality of cardiopulmonary injury. However, the potential mediators of pulmonary injury in PM2.5‐induced cardiovascular disorder are not fully understood. To investigate a potential cross talk between lung and heart upon PM2.5 exposure, intratracheal instillation in vivo, organ culture ex vivo and human bronchial epithelial cells (Beas‐2B) culture in vitro experiments were performed respectively. The exposed supernatants of Beas‐2B were collected to treat primary neonatal rat cardiomyocytes (NRCMs). Upon intratracheal instillation, subacute PM2.5 exposure caused cardiac dysfunction, which was time‐dependent secondary to lung injury in mice, thereby demonstrating a cross‐talk between lungs and heart potentially mediated via small extracellular vesicles (sEV). We isolated sEV from PM2.5‐exposed mice serum and Beas‐2B supernatants to analyse the change of sEV subpopulations in response to PM2.5. Single particle interferometric reflectance imaging sensing analysis (SP‐IRIS) demonstrated that PM2.5 increased CD63/CD81/CD9 positive particles. Our results indicated that respiratory system‐derived sEV containing miR‐421 contributed to cardiac dysfunction post‐PM2.5 exposure. Inhibition of miR‐421 by AAV9‐miR421‐sponge could significantly reverse PM2.5‐induced cardiac dysfunction in mice. We identified that cardiac angiotensin converting enzyme 2 (ACE2) was a downstream target of sEV‐miR421, and induced myocardial cell apoptosis and cardiac dysfunction. In addition, we observed that GW4869 (an inhibitor of sEV release) or diminazene aceturate (DIZE, an activator of ACE2) treatment could attenuate PM2.5‐induced cardiac dysfunction in vivo. Taken together, our results suggest that PM2.5 exposure promotes sEV‐linked miR421 release after lung injury and hereby contributes to PM2.5‐induced cardiac dysfunction via suppressing ACE2.

Cardiovascular disease is the leading cause of human death worldwide. Autophagy is an evolutionarily conserved degradation pathway, which is a highly conserved cellular degradation process in which lysosomes decompose their own organelles and recycle the resulting macromolecules. Autophagy is critical in maintaining cardiovascular homeostasis and function, and excessive or insufficient autophagy or autophagic flux can lead to cardiovascular disease. Enormous evidence indicates that exercise training plays a beneficial role in the prevention and treatment of cardiovascular diseases. The regulation of autophagy during exercise is a bidirectional process. For cardiovascular disease caused by either insufficient or excessive autophagy, exercise training restores normal autophagy function and delays the progression of cardiovascular disease. An in-depth exploration and discussion of exercise-mediated regulation of autophagy in the cardiovascular system can broaden our view about the prevention of various autophagy-related diseases through exercise training. In this article, we review autophagy and its related signaling pathways, as well as autophagy-dependent beneficial effects of exercise in cardiovascular system.

Summary: Human pluripotent stem cell (hPSC) technology has offered nearly infinite opportunities to model all kinds of human diseases in vitro. Cardiomyocytes derived from hPSCs have proved to be efficient tools for cardiac disease modeling, drug screening and pathological mechanism studies. In this review, we discuss the advantages and limitations of 2D hPSC-cardiomyocyte (hPSC-CM) system, and introduce the recent development of three-dimensional (3D) culture platforms derived from hPSCs. Although the development of bioengineering technologies has greatly improved 3D platform construction, there are certainly challenges and room for development for further in-depth research.

Circular RNAs take crucial roles in several pathophysiological processes. The regulatory role and its underlying mechanisms of circ-ZNF609 in the heart remains largely unknown. Here, we report that circ-ZNF609 is upregulated during myocardial ischemia/reperfusion (I/R) remodeling. Knockdown of circ-ZNF609 protects against acute I/R injury and attenuates left ventricle dysfunction after I/R remodeling in vivo. In vitro, circ-ZNF609 regulates cardiomyocyte survival and proliferation via modulating the crosstalk between Hippo-YAP and Akt signaling. Mechanically, N6-methyladenosine-modification is involved in the regulatory role of circ-ZNF609 on YAP. An in-depth study indicates that knockdown of circ-ZNF609 decreases the expression of YTHDF3 and further fine-tuned the accessibility of Yap mRNA to YTHDF1 and YTHDF2 to regulate YAP expression. circ-ZNF609 knockdown represents a promising therapeutic strategy to combat the pathological process of myocardial I/R injury.