The adult mammalian heart exhibits a severely limited regenerative capacity, making myocardial injury a major clinical challenge. Enhancing cardiomyocyte proliferation has emerged as a promising strategy for cardiac repair and regeneration. In this study, we identify aldolase C (ALDOC), a key glycolytic enzyme, whose expression progressively declines during postnatal heart development but is reactivated following neonatal myocardial injury. Cardiomyocyte-specific knockdown of ALDOC impairs cardiomyocyte proliferation and inhibits heart regeneration in neonatal mice after apical resection. Conversely, AAV9-mediated ALDOC overexpression markedly enhances cardiac regeneration and functional recovery in adult mice following myocardial infarction. Mechanistically, ALDOC interacts with RNA-binding motif protein 39 (RBM39) and inhibits TRIM25-mediated ubiquitination and degradation of RBM39, thereby activating PI3K/AKT signaling and promoting cardiomyocyte proliferation. In conclusion, ALDOC is a critical regulator of heart regeneration through the RBM39/PI3K/AKT pathway, and targeted activation of ALDOC or RBM39 represents a potential therapeutic strategy for myocardial injury.

Background: Radiation-induced pulmonary fibrosis (RIPF) is a common complication in patients with thoracic malignancies undergoing radiotherapy, characterized by poor prognosis and limited therapeutic options. In recent years, the study of RIPF has attracted more attention. However, this area lacks a bibliometric analysis. This study uses bibliometric analysis to examine evolving trends and core themes in RIPF research from 2015 to 2025, while forecasting future research directions. Methods: This paper conducted a search in the Web of Science and Scopus databases for publications on RIPF from 2015 to 2025. Bibliometric and visualization analyses were carried out using VOSviewer, CiteSpace, and the "bibliometrix" package in R, with particular attention to research output by countries/ regions, institutions, authors, journals, and keywords. Results: A total of 542 articles were identified in this study, with a steady increase observed in annual publications. China was the most productive country, and the United States was the core of international cooperation; the University of Maryland was the institution with the most publications and citations; the International Journal of Radiation Oncology Biology Physics published the most papers. Keyword analysis indicates a shift from experimental exploration toward clinical optimization. Recently, epithelialmesenchymal transition (EMT) has emerged as a prominent focus of research. Conclusions: Research on the prevention and treatment of RIPF holds significant clinical relevance and promising prospects. Future studies are expected to identify key regulatory nodes, refine intervention pathways, and facilitate the efficient translation of mechanistic insights into therapeutic strategies.

Preclinical research has demonstrated that vericiguat can improve myocardial microcirculation. However, real-world evidence of using vericiguat alongside guideline-directed medical therapy (GDMT) in patients with acute coronary syndrome (ACS) complicated by heart failure with reduced ejection fraction (HFrEF) remains limited. In this prospective cohort study, 149 ACS patients with left ventricular ejection fraction (LVEF) below 45

Cardiovascular disease (CVD), particularly myocardial infarction (MI), remains a leading cause of morbidity and mortality worldwide. The irreversible loss of cardiomyocytes (CMs) and subsequent fibrosis following MI due to delayed or absent reperfusion are central drivers of heart failure progression. Recent evidence indicates that the adult mammalian heart retains a latent regenerative capacity, which can be reactivated under specific conditions. Therefore, stimulating endogenous cardiac regeneration represents a promising strategy to improve clinical outcomes following MI. This review summarizes a range of intervention strategies designed to wake up cardiac regeneration and promote myocardial repair in the setting of residual following myocardial injury. Key approaches examined include stimulating cardiomyocyte cell-cycle re-entry, leveraging growth factors and paracrine mediators as pro-regenerative signals, and applying cell-free vesicles and small molecule compounds. We discuss the translational progress of these strategies, drawing on evidence from large animal models and ongoing clinical trials, aiming to bridge mechanistic discoveries to future clinical applications in cardiac regenerative medicine.

With the acceleration of global population aging, the progressive deterioration of cardiac structure and function has become a critical determinant of cardiovascular health, presenting a significant public health challenge. Checkpoint kinase 1 (CHK1), a key cell cycle checkpoint protein, plays an essential role in various biological processes by mediating signaling cascades. While CHK1 has been shown to be important for heart regeneration, its role in the aging process of the heart remains unclear. In this study, we investigated the alterations in CHK1 expression in aging hearts and elucidated the underlying regulatory mechanisms. In both in vivo and in vitro models, CHK1 expression was significantly downregulated during aging. To assess its functional role, we generated cardiomyocyte-specific CHK1 overexpression and knockout mice and compared their cardiac performance. We found that CHK1 overexpression alleviated age-associated cardiac dysfunction, while CHK1 knockout worsened cardiac function in aged mice. Furthermore, CHK1 overexpression significantly attenuated doxorubicin (DOX)-induced acutely senescence in adult mouse cardiomyocytes (AMCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Mechanistic studies revealed that CHK1 overexpression delayed cardiac aging by activating heat shock protein 90 (HSP90)-mediated mitophagy. Immunoprecipitation and mass spectrometry (IP-MS) analyses demonstrated that CHK1 directly interacts with the activator of HSP90 ATPase homolog 1 (AHSA1), thereby suppressing TRIM8-mediated ubiquitination and degradation, facilitating AHSA1-HSP90 complex formation, and enhancing HSP90 ATPase activity. Overall, our results suggest that CHK1 overexpression activates mitophagy via the AHSA1-HSP90 pathway to mitigate cardiac aging. This study highlights the critical role of CHK1 in cardiac aging and proposes a potential therapeutic strategy for aging-associated cardiomyopathy and heart failure.

Coronary artery disease (CAD) is a major cardiovascular disorder primarily caused by coronary atherosclerosis, and early, sensitive diagnosis remains a clinical challenge. In this study, we developed a novel diagnostic model for CAD and explored potential therapeutic agents. CAD-associated datasets were obtained from the Gene Expression Omnibus. Using multimachine learning algorithms, 32 CAD- and immune-related characteristic genes were identified, and the resulting diagnostic model demonstrated excellent diagnostic performance. Immune cell infiltration analysis suggested that CD8+ T cells and naive B cells were the principal immune cell populations showing abnormal alterations in peripheral blood. Furthermore, functional assays indicated that treprostinil significantly inhibited tumor necrosis factor-α-induced apoptosis in human umbilical vein endothelial cells, enhanced cell viability, and alleviated endothelial inflammatory responses. In conclusion, we established a robust CAD diagnostic model and screened potential therapeutic drugs, offering new perspectives for the diagnosis and treatment of CAD.

Background Localized aortic sinus dissection is a rare cause of acute coronary syndrome that is often undetected on initial imaging. Case Summary A 72-year-old man with aortic root aneurysm presented with acute inferior ST-segment elevation myocardial infarction (STEMI). Initial computed tomography was negative for aortic dissection, however angiography revealed total occlusion of the right coronary artery (RCA) owing to coronary artery dissection. Percutaneous coronary intervention (PCI), challenging given an anomalous RCA ostium, successfully stented the occlusion. Subsequent high-resolution coronary computed tomography angiography identified right aortic sinus intimal tears extending into the RCA ostium; retrospective review of pre-PCI imaging confirmed dissection. The patient underwent Bentall surgery with RCA bypass. Discussion This case highlights a localized aortic sinus dissection mimicking primary coronary disease, emphasizing the importance of advanced imaging and the role of adaptive PCI as a bridge to definitive surgery. Take-Home Messages Localized aortic sinus dissection can mimic acute STEMI and should be considered in patients with known aortic root disease, even when initial imaging appears unremarkable. High-resolution coronary computed tomography angiography is diagnostic; PCI for anomalous ostia may require advanced techniques. A heart team approach is vital for staged management.

Background The gut microbiota plays a significant role in the incidence and progression of colorectal cancer(CRC), with Fusobacterium nucleatum (F. nucleatum) identified as a contributor to the advancement of this malignancy. However, the precise mechanisms underlying its action remain unclear. Methods This study uses FISH technology to measure F. nucleatum in tumors and WB to examine histone lactylation, exploring their connection. HCT116 CRC cells were treated with lactic acid, Oxamate, 2-DG, and F. nucleatum supernatant to analyze histone lactylation and cell behaviors like proliferation, migration, and invasion. The research also screened F. nucleatum supernatant for compounds that increase tumor cell lactylation and assessed their effects on cell viability using CCK-8, EdU, and transwell assays. Additionally, GLUT agonists and inhibitors were used to demonstrate that formic acid in the supernatant elevates GLUT1 expression. Results Tumors characterized by elevated nuclear levels demonstrate increased histone lactylation. Modulating histone lactylation levels in tumor cells through human intervention can substantially impact their proliferative, migratory, and invasive capacities. Our study identified that F. nucleatum enhances the expression of GLUT1 in tumor cells via its metabolite, formic acid, leading to increased lactate production and histone lactylation. This process ultimately augments the stemness of tumor cells. Conclusions F. nucleatum enhances the expression of GLUT1 in colorectal cancer cells through the production of formic acid, which subsequently elevates histone lactate levels and facilitates tumor progression.

Myocardial infarction (MI) is a major driver of left atrial dysfunction and structural remodeling, substantially increasing the risks of heart failure and stroke. Frailty, a common geriatric syndrome, has been linked to adverse cardiovascular outcomes, but its mechanistic contribution remains poorly defined. This study examined the impact of frailty on left atrial remodeling after MI in aged mice and explored the underlying mechanisms. Frailty was modeled in 24-month-old IL-10 knockout mice, and MI was induced by permanent ligation of the left anterior descending coronary artery. Cardiac structure and function were evaluated by echocardiography and histological analysis. In vitro, frailty enhances the susceptibility of atrial cardiomyocytes to pathological remodeling under combined senescent and ischemic stress. RNA-seq of left atrial tissue from wild-type and frail mice after MI was performed, and key findings were validated by quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence. Although frailty had no baseline effect on left atrial structure or function, frail mice developed pronounced left atrial dilation, increased fibrosis and inflammation, and reduced survival 28 days after MI. Transcriptomic analysis showed enrichment of pyroptosis-, immune activation-, and cytokine signaling-related pathways, with robust activation of NLR and AIM2 inflammasomes. Pharmacological inhibition with the dual NLRP3 and AIM2 inflammasome inhibitor NLRP3/AIM2-IN-3 attenuated cardiomyocyte pyroptosis, reduced myocardial inflammation and pathological remodeling, and improved left atrial function. These findings demonstrate that frailty exacerbates post-MI left atrial remodeling and dysfunction in aged mice by promoting inflammasome-mediated pyroptosis and identify NLRP3/AIM2-IN-3 as a promising therapeutic strategy for frailty-associated left atrial injury.

The non-high-density lipoprotein to high-density lipoprotein cholesterol ratio (NHHR) is an emerging lipid index linked to cardiovascular and metabolic risk. High-sensitivity C-reactive protein (hs-CRP) serves as a well-established marker of systemic inflammation. However, the association between NHHR and hs-CRP in the general population remains unclear. This study aimed to investigate their relationship using nationally representative US data. We analyzed data from 5994 adults aged ≥20 years from the 2015 to 2018 National Health and Nutrition Examination Survey (NHANES). NHHR was calculated as (total cholesterol - high-density lipoprotein cholesterol [HDL-C])/high-density lipoprotein cholesterol. Survey-weighted multivariable linear regression models were used to evaluate the association between NHHR (both continuous and quartiles) and hs-CRP levels. Restricted cubic spline analysis assessed nonlinear patterns. Subgroup and interaction analyses were conducted by age, sex, body mass index, diabetes, and hypertension. After full adjustment, NHHR was positively associated with hs-CRP (β = 0.91, 95% CI: 0.42-1.40, P = .002). Participants in Q3 and Q4 had significantly higher hs-CRP levels than those in Q1. Restricted cubic spline analysis revealed a significant nonlinear (inverted U-shaped) relationship (P for nonlinearity < .001). Subgroup analyses showed stronger associations in women and individuals with hypertension (P for interaction < .05). In this exploratory, cross-sectional analysis, our findings suggest that NHHR may be independently associated with hs-CRP and may exhibit a nonlinear relationship in US adults, suggesting its potential utility as an accessible marker of low-grade systemic inflammation; however, longitudinal cohort studies are needed to confirm these associations and to evaluate its potential predictive value and clinical applicability.

ABSTRACT Myocardial infarction (MI) often results in significant loss of cardiomyocytes (CMs), contributing to adverse ventricular remodelling and heart failure. Therefore, promoting CM survival during the acute stage of MI is crucial. This study aimed to investigate the potential role of GPX3 in cardiac repair following MI. First, plasma GPX3 levels were measured in patients with acute MI (AMI), and myocardial GPX3 expression was assessed in a mouse MI model. Furthermore, the effects of GPX3 on MI were investigated through CM‐specific overexpression or knockdown in vitro and in vivo models. RNA sequencing and subsequent experiments were performed to uncover the molecular mechanisms underlying GPX3‐related effects. Multi‐omics database analysis and experimental verification revealed a significant upregulation of GPX3 expression in ischemic myocardium following MI and in CMs exposed to oxygen–glucose deprivation (OGD). Immunofluorescence results further confirmed elevated cytoplasmic GPX3 expression in CMs under hypoxic conditions. In vitro, GPX3 overexpression mitigated reactive oxygen species (ROS) production and enhanced CM survival during hypoxia, while GPX3 knockdown inhibited these processes. In vivo, CM‐specific GPX3 overexpression in the infarct border zone significantly attenuated CM apoptosis and alleviated myocardial injury, promoting cardiac repair and long‐term functional recovery. Mechanistically, GPX3 overexpression upregulated LSD1 and Hif1α protein expression, and rescue experiments confirmed the involvement of the LSD1/Hif1α pathway in mediating the protective effects of GPX3. Overall, our findings suggest that GPX3 exerts a protective role in ischemic myocardium post‐MI, at least partially through the LSD1/Hif1α axis, highlighting its potential as a therapeutic target for MI treatment.

Objective: As one of the classic cell cycle checkpoint proteins, Checkpoint kinase 1 (CHK1) extensively participates in various biological processes primarily through mediating a cascade of reactions. Although previous studies have identified CHK1 as a critical factor in myocardial regeneration repair, its role in the natural senescence process of heart in mice remains unclear. Methods: Firstly, the expression of CHK1 was detected in models of cardiomyocyte senescence by doxorubicin (DOX) and in natural senescence mice. Secondly, cardiomyocyte-specific CHK1 overexpression and knockdown were constructed to explore the effect on natural cardiac senescence. Subsequently, the role of CHK1 was investaged in DOX-induced AC16. Finally, the molecular mechanism by which CHK1 attenuates cardiac senescence in aged mice was elucidated by combining transcriptomic sequencing (RNA-seq) and Co-immunoprecipitation coupled with mass spectrometry (IP/MS). Results: CHK1 expression was significantly downregulated in both in vivo and in vitro senescence models. CHK1 overexpression attenuated cardiac senescence in aged mice, while CHK1 knockout had opposite impact. Overexpression of CHK1 markedly improved senescence of DOX-induced AC16 in vivo. RNA-seq reveled that CHK1 overexpression activates heat shock protein 90 (HSP90)-mediated mitophagy. IP/MS demonstrated that CHK1 specifically binds to the activator of 90kDa heat shock protein ATPase homolog 1 (AHSA1). Mechanistically, CHK1 activates HSP90-mediated mitophagy by binding to AHSA1 and inhibiting its ubiquitination-mediated degradation. Conclusion: CHK1 activates mitophagy to attenuate cardiac senescence through binding to AHSA1 and inhibiting its ubiquitination-mediated degradation in aged mice. Our study reveals the significant role of CHK1 in the natural senescence process of heart and provides a potential therapeutic target for the treatment of age-related cardiac diseases in the future.

Background: Neonatal heart possesses a unique ability to regenerate within seven days of birth. However, the adult mammalian heart is incapable of regeneration. The underlying related mechanisms affecting cardiomyocyte proliferation and heart regeneration remain to be explored. Methods: Primary cardiomyocytes and hearts from neonatal (P1) mice and adult (P56) mice were used to investigate potential hub proteins involved in heart regeneration. High mobility group box 2 (HMGB2) was identified through using quantitative proteomics with tandem mass tag labeling, RNA-sequencing (RNA-seq) and single-nucleus RNA-seq dataset analyses. Cardiomyocyte-specific HMGB2 knockdown mice and cardiomyocyte-specific HMGB2 overexpression mice were used to evaluate the role of HMGB2 in heart regeneration in vivo. RNA-sequencing analysis was then conducted to identify transcriptome changes associated with HMGB2 in cardiomyocytes. Immunoprecipitation coupled with mass spectrometry and co immunoprecipitation were used to uncover Metastasis-associated protein 2 (MTA2) as a downstream target of HMGB2. Results: HMGB2 was identified as a key regulator of cardiomyocyte proliferation, whose expression declines during postnatal heart development and increases in the high regenerative potential cardiomyocyte populations in hearts post-injury. Cardiomyocyte-specific HMGB2 knockdown curtailed cardiomyocyte proliferation and impaired heart regeneration following apical resection (AR) in neonatal mice, while cardiomyocyte-specific HMGB2 overexpression enhanced cardiomyocyte proliferation and facilitated heart regeneration post-myocardial infarction in adult mice. Mechanistically, RNA-seq analysis revealed that HMGB2 promotes cardiomyocyte proliferation via activating HIF-1α-mediated glycolysis. This study further found HMGB2 can directly interact with metastasis-associated protein 2 (MTA2) and inhibit its ubiquitination degradation to stabilize HIF-1α protein through immunoprecipitation-mass spectrometry (IP-MS) analysis. Finally, activating HIF-1α or MTA2 could also promote heart regeneration post-myocardial infarction. Conclusions: HMGB2 plays a crucial role in promoting heart regeneration through regulating glycolysis. Activating the HMGB2-MTA2 axis might serve as potential therapeutic options for regenerative therapies post-myocardial injury.

The neonatal heart possesses the unique ability to regenerate post-injury. Underlying related mechanisms and reactivation of this process are crucial for regeneration medicine. Using quantitative proteomics with tandem mass tag labeling, RNA-sequencing (RNA-seq) and single-nucleus RNA-seq dataset analyses, high mobility group box 2 (HMGB2) is identified as a key regulator of cardiomyocyte proliferation, whose expression declines during postnatal heart development and increases in the high regenerative potential cardiomyocyte populations in hearts post-injury. Cardiomyocyte-specific HMGB2 knockdown curtails cardiomyocyte proliferation and impairs heart regeneration following apical resection in neonatal mice, while cardiomyocyte-specific HMGB2 overexpression enhances cardiomyocyte proliferation and facilitates cardiac regeneration and repair in adult mice post-myocardial infarction. Mechanistically, RNA-seq analysis reveals that HMGB2 promotes cardiomyocyte proliferation via activating hypoxia inducible factor 1ɑ (HIF-1α)-mediated glycolysis. This study further finds HMGB2 can directly interact with metastasis-associated protein 2 (MTA2) and inhibit its ubiquitination degradation to stabilize HIF-1α protein through immunoprecipitation-mass spectrometry (IP-MS) analysis. Finally, overexpression of HIF-1α or MTA2 also promotes cardiomyocyte proliferation and cardiac repair in adult mice following MI. Taken together, these findings highlight that HMGB2 plays a crucial role in promoting heart regeneration through regulating glycolysis. Activating the HMGB2-MTA2-HIF-1α axis might serve as a potential therapeutic option for regenerative therapies post-myocardial injury.

BACKGROUND:Glyphosate is the most widely used herbicide globally. However, its association with frailty, an emerging public health concern, and mortality in the general population remains unclear. METHODS:This cohort utilized the National Health and Nutrition Examination Survey (NHANES) 2013-2018 data, with follow-up through December 31, 2019. Weighted logistic regression, Cox regression, and restricted cubic splines analyses were performed to investigate the association of urinary glyphosate with frailty, defined using a 49-item frailty index at baseline, and all-cause mortality, respectively. Causal mediation analysis and sensitivity analysis were also employed. RESULTS:4697 adults (mean age: 47.1 years; 48.9 % male) were included. Multivariable logistic regression showed that elevated urinary glyphosate correlated with increased frailty prevalence (log2-transformed, adjusted OR = 1.14, 95 % CI: 1.04-1.25; quartiles, P for trend = 0.002), with a linear dose-response relationship (P value for nonlinearity = 0.568). During a median follow-up of 3.9 years, 238 total deaths occurred. Multivariable-adjusted Cox regression demonstrated that urinary glyphosate was positively related to all-cause mortality (log2-transformed, adjusted HR = 1.19, 95 % CI: 1.07-1.31; quartiles, P for trend = 0.005). Additionally, frailty significantly mediated the association between glyphosate and all-cause mortality, with mediation proportion of 30.3 %. CONCLUSIONS:Urinary glyphosate was positively associated with frailty and all-cause mortality in the general US adult population. Frailty also played a partial mediator role in this relationship. These findings provide new evidence of adverse health effects of glyphosate and imply that enhanced efforts should be made to mitigate exposure to glyphosate.

Background Abdominal aortic aneurysm (AAA) is a clinical life‐threatening issue. No pharmacological treatments are currently approved for the prevention and treatment of AAA. Therefore, identifying novel biomarkers and therapeutic targets is crucial for improving AAA management and outcomes. Methods To identify plasma proteins with potential causal effects on AAA, we integrated genetic evidence from proteome‐wide Mendelian randomization, genetic correlation, and colocalization analysis. The role of identified proteins in AAA was further explored through the phenome‐wide association study and mediation analysis. Multiomics data analysis, including bulk RNA sequencing, single‐cell/single‐nucleus RNA sequencing, and spatial transcriptomics, was employed to characterize the expression patterns of these proteins. Experimental validation was performed using an AAA model in apolipoprotein E‐deficient mice infused with angiotensin II. Druggability analysis was conducted to identify drug candidates, which were tested in preclinical mouse models. Results CALB2 (calbindin 2) was identified as having a causal effect on AAA and may influence the progression of AAA through the regulation of lipid metabolism. Multiomics analysis revealed that CALB2 is predominantly expressed in the mesothelial cells of adipose tissues. Inhibition of CALB2 in an AAA mouse model alleviated AAA progression. Druggability analysis identified lenalidomide and genistein as potential therapeutic candidates, and experiments confirmed their efficacy in preventing AAA development. Conclusions This study identifies CALB2 as being associated with an increased risk of AAA and suggests that i might be a novel biomarker and therapeutic molecule for AAA management. Lenalidomide and genistein hold promising potential as treatments for patients with AAA.

Cardiac fibrosis following myocardial infarction (MI) is a pivotal driver of ventricular dysfunction and heart failure, yet the molecular checkpoints orchestrating the persistent activation of cardiac fibroblasts remain incompletely defined. Here, we uncover a non-canonical, metabolism-independent function of Uridine-Cytidine Kinase 2 (UCK2) and Uridine-Cytidine Kinase Like-1 (UCKL1) as synergistic regulators of pathological remodeling. We demonstrate that both proteins are robustly upregulated in the border zone of ischemic murine hearts and transforming growth factor-β (TGF-β)-activated human cardiac fibroblasts (HCFs). Mechanistically, UCK2 and UCKL1 physically assemble into an obligate functional complex that acts as a molecular scaffold rather than a metabolic enzyme. This complex recruits the E3 ubiquitin ligase Tripartite Motif Containing 21 (TRIM21) to orchestrate the specific ubiquitination and degradation of the negative regulator SMAD Specific E3 Ubiquitin Protein Ligase 2 (Smurf2), thereby sustaining SMAD Family Member 3 (Smad3) phosphorylation and amplifying fibrogenic TGF-β signaling. Disruption of this axis via combined genetic silencing exerts a synergistic protective effect by abrogating myofibroblast differentiation and extracellular matrix production. Furthermore, therapeutic intervention using adeno-associated virus (AAV)-mediated knockdown of UCK2/UCKL1 significantly attenuates adverse ventricular remodeling, limits scar expansion, and preserves cardiac function in a murine MI model. Collectively, these findings identify the UCK2/UCKL1-TRIM21-Smurf2-Smad3 axis as a novel, druggable signalosome linking kinase “moonlighting” functions to transcriptional reprogramming, offering a transformative therapeutic strategy to arrest the progression of post-ischemic heart failure.

Background: Vericiguat has been approved in stable chronic heart failure with reduced ejection fraction (HFrEF). However, its efficacy in acute coronary syndrome (ACS) combined with left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF) <45%) remains unclear. Hypothesis: In ACS patients with LVEF <45%, vericiguat combined with guideline-directed medical therapy (GDMT) can significantly reduce the risk of cardiovascular death or heart failure rehospitalization compared to GDMT alone. Methods: This single-center, prospective, randomized controlled trial enrolled 144 patients with ACS and LVEF <45%. Participants were randomly assigned in a 1:1 ratio to either vericiguat combined with GDMT group (target dose: 10 mg once daily) or GDMT alone for 12 months. The primary endpoint was the composite outcome of cardiovascular death or first hospitalization for heart failure. Secondary endpoints included dynamic changes in LVEF, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (KCCQ-CSS), quality of life score (KCCQ-QoL), and total symptom score (KCCQ-TSS) during follow-up. Efficacy was assessed using intention-to-treat analysis. Results: During a median follow-up of 12 months, the primary outcome occurred in 4/72 (5.6%) patients in the vericiguat + GDMT group and 15/72 (20.8%) in the GDMT group (hazard ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.75; P=0.008). For secondary endpoints, significant differences in NT-proBNP were observed between groups at 1 month (log-transformed mean difference [MD], 0.544; 95% CI,-0.97 to -0.12; P= 0.014) and persisted until study end (MD, 0.644; 95% CI,-1.11 to -0.58; P = 0.004). At 6 months, LVEF improved by 2.70% in the vericiguat + GDMT group compared to GDMT (95% CI, 1.56 to 4.45; P=0.030). No significant between-group difference was observed in the KCCQ-CCS (P=0.103).However, after 3 months, vericiguat + GDMT group demonstrated significant improvements in KCCQ-QoL（P=0.008) and KCCQ-TSS（P=0.020) compared with the GDMT group, with sustained benefits through subsequent follow-up. Conclusions: On the basis of GDMT, vericiguat significantly reduces cardiovascular death or heart failure rehospitalization risks and improves left ventricular systolic function and quality of life in ACS patients with LVEF <45%. (ClinicalTrials.gov number, NCT06321094).

AIMS:Alcoholic liver disease (ALD) is characterized by aberrant lipid metabolism and chronic inflammation that eventually give rise to cirrhosis and hepatocellular carcinoma. In the present study we investigated the contribution of CC motif chemokine ligand 11 (CCL11) to ALD pathogenesis. METHODS AND MATERIALS:ALD was induced in mice by binge ethanol gavage or chronic ethanol feeding. KEY FINDINGS:Bioinformatic analysis of sequencing data indicated that CCL11 expression was up-regulated in hepatocytes from mice subjected to ethanol feeding compared to those from the control mice. Exposure to ethanol led to CCL11 up-regulation in primary murine hepatocytes in vitro. Consistently, Oil Red O (ORO) staining detected elevated lipid accumulation whereas quantitative PCR (qPCR) detected augmented expression of pro-inflammatory mediators in primary murine hepatocytes treated with recombinant CCL11. On the contrary, CCL11 knockout mice (KO) developed a less severe form of ALD compared to wild type littermates when subjected to either binge or chronic ethanol feeding. Finally, CCL11 antagonism by administration with an inhibitor to CCL11 receptor CCR3 (CCR3i) attenuated ALD in mice. SIGNIFICANCE:Our data support a role for CCL11 in ALD pathogenesis and provide proof-of-concept that targeting CCL11 can be considered as a therapeutic approach for ALD intervention.

BACKGROUND:Microsatellite stability influences the prognosis of patients with colorectal cancer (CRC). However, there are few studies on the relationship between microsatellite stability and lymph node metastasis (LNM) in CRC. OBJECTIVE:This study aims to elucidate the relationship between microsatellite stability and LNM in CRC and to investigate potential underlying mechanisms. METHODS:A retrospective analysis was performed on a cohort of 309 CRC patients, who were categorized into microsatellite instability (MSI) and microsatellite stability (MSS) groups based on their microsatellite status. Clinical and pathological indicators were collected, and differences between the two groups were assessed. The tertiary lymphoid structures (TLS) in both groups were examined using immunohistochemistry and immunofluorescence to compare differences in density, maturity, and the ratio of CD8+T cells. Establishing the relationship between microsatellite stability, TLS characteristics, and lymph node metastasis. RESULTS:The TNM staging for patients in the MSI group was significantly earlier compared to those in the MSS group. Subsequent analysis of pathological indicators demonstrated that the MSI group exhibited a significantly lower incidence of lymph node metastases (31.4% vs. 47%, P=0.005), while no statistically significant differences were observed in other pathological indicators (P>0.05). Examination of CRC tissue sections revealed that the MSI group possessed a greater number and maturity of tertiary lymphoid structures, as well as a higher proportion of CD8+T cells. CONCLUSION:MSI may decrease the incidence of LNM in CRC, potentially as a result of the activation of local anti-tumor immune responses facilitated by MSI.