BACKGROUND:Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality worldwide, and an urgent need exists to discover new therapeutic strategies. Isolinderalactone (ISO) is a sesquiterpene compound derived from the Lindera aggregata root with significant anti-inflammatory effects. Given that atherosclerosis (AS) is a chronic inflammatory condition, the efficacy and mechanism of ISO on atherosclerotic disease are still unclear. PURPOSE:The study aims to evaluate the therapeutic potential of ISO as an NLRP3 inhibitor in the management of AS. METHODS:For in vivo study, ApoE-/- mice were fed a high-fat diet to induce an AS model to evaluate the therapeutic effect of ISO. For in vitro study, bone marrow-derived macrophages (BMDMs) were used to elucidate the specific molecular mechanism by which ISO inhibits NLRP3 inflammasome activation. Mass spectrometry and molecular docking analyses were conducted to identify active sites. RESULTS:Our data show that ISO reduced atherosclerotic plaque formation by inhibiting NLRP3 inflammasome activation and inflammatory responses. Network pharmacology analyses showed that ISO might alleviate AS by suppressing the NOD-like receptor (NLR) pathway, leading to reduced inflammatory mediators. ISO dose-dependently suppressed IL-1β secretion through inhibiting NLRP3 inflammasome activation, displaying an IC50 value of 2.882 μM. In addition, ISO selectively blocked ASC oligomer formation and disrupted NLRP3 inflammasome complex assembly. Mass spectrometry and docking simulations revealed that ISO formed covalent bonds with the NLRP3 protein, specifically targeting Cys470 within its NACHT domain. CONCLUSION:Collectively, ISO emerges as a novel NLRP3 inhibitor and a potential therapeutic candidate for atherosclerotic disease.

Migraine is a prevalent neurological disorder, but the systemic molecular alterations that precede its onset and their biological relevance remain incompletely understood. We conducted a prospective plasma proteomics analysis among 50,668 migraine-free participants from the UK Biobank. Baseline levels of 2,923 plasma proteins were quantified using the Olink Explore platform. Multivariable Cox proportional hazards models were applied to assess associations between protein levels and incident migraine during follow-up, with adjustment for demographic, lifestyle, and clinical covariates. False discovery rate (FDR) correction was used to account for multiple testing. Trajectory analyses were performed to characterize temporal protein patterns prior to diagnosis. Functional enrichment, protein–protein interaction, and transcription factor analyses were conducted to explore biological pathways. Single-cell transcriptomic data were integrated to assess cell-type specificity. Genetic analyses, including polygenic risk score associations, Mendelian randomization, and Bayesian colocalization, were used to evaluate potential causal relationships. Associations between migraine-related proteins and global brain structural measures derived from magnetic resonance imaging were examined. Machine-learning models were developed to evaluate the predictive performance of plasma proteomic profiles for future migraine risk. After FDR correction, 126 proteins were significantly associated with incident migraine, of which 124 were retained for downstream analyses. Distinct protein trajectories were observed several years before clinical diagnosis. Enrichment analyses consistently implicated immune regulation and neuro-immune signaling pathways. Genetic analyses supported potential causal roles for a subset of proteins, and several migraine-associated proteins were linked to global brain structural measures. Proteomics-based models achieved modest but reproducible discrimination of future migraine risk. These findings demonstrate that migraine is preceded by long-term systemic proteomic alterations, highlight immune-related molecular pathways and genetically supported proteins potentially involved in migraine pathogenesis, and provide a foundation for future mechanistic studies and early risk stratification strategies. Not applicable.

Here, we present a computational workflow for identifying and analyzing the molecular mechanisms through which environmental pollutants may contribute to human diseases. We describe steps for integrating network toxicology and molecular docking to enable systematic prediction of pollutant-target-disease relationships and structure-based plausibility assessment of molecular interactions. This protocol provides a reproducible and scalable framework applicable to diverse environmental compounds and disease models.

Endocrine-disrupting chemicals (EDCs) are increasingly recognized as environmental contributors to hepatocellular carcinoma (HCC), yet their molecular mechanisms remain poorly understood. This study integrates toxicogenomic, transcriptomic, genetic, and single-cell RNA sequencing data to elucidate how EDCs reprogram hepatic metabolic and immune networks to promote tumorigenesis. By intersecting 5797 EDC-responsive genes with 946 HCC differentially expressed genes, 513 overlapping candidates were identified, enriched in pathways involving hormone signaling, xenobiotic metabolism, lipid regulation, and inflammation. Genetic evidence supported five genes (ESR1, TP53I3, PLIN2, SLC6A12, and SOCS2) as key determinants of HCC susceptibility. These genes exhibited experimentally supported interactions with multiple EDCs, including bisphenol A, diethylhexyl phthalate, and cadmium chloride, implicating them as convergent molecular targets of environmental exposures. Single-cell transcriptomic analysis revealed cell-type-specific expression, notably SOCS2 in endothelial cells and PLIN2 in myeloid populations, while ESR1 displayed sex-dimorphic expression patterns consistent with disrupted estrogen signaling in female HCC. These findings indicate that chronic EDC exposure perturbs hormonal, metabolic, and immune homeostasis, driving hepatic carcinogenesis through coordinated gene network reprogramming. The integrative multi-omics framework presented here provides novel mechanistic insight into the environmental etiology of liver cancer and identifies candidate biomarkers for exposure-linked prevention strategies.

Background:Oral microbiome diversity has been associated with general health. However, its association with long-term outcomes in hypertensive individuals remains unclear. Objectives:This study aimed to investigate whether oral microbiome diversity is associated with all-cause mortality in hypertensive individuals. Design:Data from 2,669 hypertensive individuals in the National Health and Nutrition Examination Survey (NHANES, 2009-2012) were analyzed. Oral microbiome diversity was assessed using four alpha-diversity metrics: the Simpson index, Shannon-Weiner index, Faith's Phylogenetic Diversity, and observed amplicon sequence variants (ASVs). Weighted multivariable Cox proportional hazards regression and interaction analyses were conducted. Results:During a mean follow-up of 8.61 years, 268 all-cause deaths occurred. Higher oral microbiome diversity assessed by the Simpson index (hazard ratio [HR] = 0.38; 95% confidence interval [CI], 0.20-0.75; P trend < 0.01) and Shannon-Weiner index (HR = 0.47; 95% CI, 0.25-0.88; P trend < 0.05), was significantly associated with reduction in all-cause mortality risk. A potential interaction between sex and oral microbiome diversity on mortality risk was observed. Conclusions:Higher oral microbiome diversity is an independent protective factor for survival in patients with hypertension, with potential sex-specific differences in this association. These findings suggest that enhancing oral microbiome diversity may potentially help promote overall health in individuals with hypertension.

Abstract Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with limited therapeutic options. Disulfidptosis, a novel cell death modality triggered by disulfide stress, represents a promising therapeutic target. While CAPZB has been implicated in disulfidptosis, its role in ICC remains undefined. This study investigates whether CAPZB regulates disulfidptosis via SQOR to promote ICC progression. Methods: Transcriptomic analysis of three ICC cohorts (n=98) and single-cell RNA-seq (n=4) evaluated CAPZB expression and prognostic significance. CAPZB was genetically modulated in ICC cell lines using shRNA/overexpression constructs. Disulfidptosis was induced by glucose deprivation and assessed via cell viability, F-actin staining, and NADP+/NADPH/GSH/GSSG ratios. Protein interactions were identified by IP-MS and validated by co-immunoprecipitation. AKT/NICD mouse models evaluated in vivo tumor progression. Patient-derived organoids were treated with GLUT1 inhibitor BAY-876. Results: CAPZB was significantly overexpressed in ICC tissues and correlated with poor overall survival (p<0.01). Single-cell analysis revealed elevated CAPZB in malignant cholangiocytes. CAPZB knockdown suppressed proliferation, migration, and invasion, while overexpression enhanced malignant phenotypes. IP-MS identified SQOR as a CAPZB-interacting protein, with strong expression correlation (p<0.001). CAPZB knockdown promoted disulfidptosis under glucose deprivation, increasing cell death (p<0.001), F-actin contraction, and NADP+/NADPH ratio. SQOR overexpression partially rescued these effects. In vivo, CAPZB knockdown reduced tumor burden (p<0.01). Patient-derived organoids showed BAY-876 sensitivity (IC50=0.315 μM). Combination therapy with CAPZB knockdown and BAY-876 demonstrated synergistic anti-tumor efficacy (p<0.001). Conclusions: CAPZB is a disulfidptosis-related oncogene that drives ICC progression by interacting with SQOR to maintain redox homeostasis and suppress disulfidptosis. Targeting CAPZB alone or with GLUT1 inhibitors induces synthetic lethality via disulfidptosis, offering a promising therapeutic strategy. Citation Format: Jiangqiao Yao, Tong Chen, Ziyan Chen, Gang Chen, Chongming Zheng, Yi Wang. CAPZB suppresses disulfidptosis through SQOR interaction to drive intrahepatic cholangiocarcinoma progression and therapeutic vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4666.

The high clinical recurrence rate of colorectal cancer (CRC) is driven by the survival of residual tumor cells that evade therapy-induced death by entering a dormant state. While dormancy is a recognized mechanism of treatment resistance, the molecular drivers governing this "quiescent reservoir" and its associated vulnerabilities remain poorly characterized, limiting the development of strategies to eradicate these dormant seeds. We developed a COAD-specific Dormancy Score (CADS) derived from NMF analysis of 69,000 single cells to quantify and identify a dormant subpopulation at single-cell resolution. Mechanistically, the IFN-β/cDC1 axis and its downstream MEK/ERK dependency were validated using a GFP-p27K- dormancy reporter system, spatial transcriptomics, and CRISPR/Cas9-mediated Ifnar1 knockdown. Finally, the synergistic efficacy of anti-PD-1 combined with MEK inhibition (Trametinib) was evaluated in orthotopic CRC mouse models. The CADS effectively identified a distinct dormant subpopulation in CRC characterized by profound G0/G1 arrest, enhanced stemness, and multi-drug resistance. We uncovered a novel evasion mechanism mediated by the hijacking of IFN-β signaling. Conventionally recognized for its anti-proliferative roles, IFN-β signaling is exploited by surviving tumor cells to enter a deep quiescent state. This phenotype acts as a biological reservoir that fuels intratumoral heterogeneity and underpins the relapse of colorectal tumors by conferring resistance to conventional cytotoxic regimens. Effective anti-PD-1 therapy paradoxically enriches this dormant population via an enhanced IFN-β-conventional type 1 dendritic cell (cDC1) axis. Mechanistically, IFN-β–induced dormancy depends on MEK/ERK pathway activity, which sustains survival while suppressing apoptosis. This creates a synthetic lethal vulnerability: MEK inhibition (e.g., Trametinib) synergizes with IFN-β to re-sensitize dormant cells to apoptosis. Consequently, combining Trametinib with anti-PD-1 therapy overcomes this evasion mechanism, eliminates the dormant subpopulation, remodels the immune microenvironment, and shows strong synergistic efficacy in preclinical models. Our work redefines an immune–cell death paradox, revealing how tumors exploit IFN-β to evade therapy. We propose CADS as a translational biomarker for identifying tumors reliant on this pathway and validate a mechanism-based combination therapy that selectively targets dormancy-associated death resistance, offering a promising strategy to improve CRC outcomes.

Rhotekin, an effector protein for Rho proteins, is implicated in tumorigenesis, yet its function in other biological processes remains largely unexplored. In the current study, we investigate the function of Rhotekin in osteoblast differentiation and bone homeostasis. Our data show that Rhotekin is expressed in bone and adipose tissue, with its levels increasing as mesenchymal progenitor cells differentiate toward both osteoblasts and adipocytes. When Rhotekin is overexpressed in progenitor cells, it facilitates osteogenic differentiation while inhibiting adipogenic differentiation, whereas knockdown of Rhotekin leads to opposite effects. Moreover, in vivo silencing of Rhotekin in bone marrow results in an increase in adipocytes and a decrease in osteoblasts, ultimately leading to a reduction in cancellous bone mass in mice. Further mechanistic investigations unveil that Rhotekin interacts with Chibby 1 (CBY1), an antagonistic regulator of β-catenin, and competes with β-catenin for binding to CBY1, thereby activating the canonical Wnt/β-catenin pathway. CBY1 is found to suppress osteoblast differentiation, an effect that is counteracted by overexpression of Rhotekin. Moreover, Rhotekin activates the focal adhesion kinase (FAK)/AKT signaling. Collectively, this study provides compelling evidence that Rhotekin interacts with CBY1, relieves its antagonistic effect on β-catenin, and thereby activates canonical Wnt/β-catenin signaling. Together with the concomitant activation of the FAK/AKT pathway, these events contribute to osteoblast differentiation and maintenance of bone homeostasis. Rhotekin may represent a promising therapeutic target for metabolic bone disorders such as osteoporosis.

BACKGROUND AND AIMS:Hypertensive heart failure has an urgent need for new therapeutic targets. Protein kinases act as key regulators in cellular actions relevant to cardiac pathophysiology. This study identified a protein kinase, Wee1 G2 checkpoint kinase (Wee1), being activated and involved in this disease. METHODS:RNA-seq-based kinase enrichment analysis was used to identify the involved kinase pathways. Cardiomyocyte-specific Wee1-deficiency mice with chronic angiotensin II (Ang II) infusion and transverse aortic constriction (TAC) were utilized to develop cardiac remodelling. RNA-seq and co-immunoprecipitation were used to explore the mechanism and substrate of Wee1. RESULTS:Kinase enrichment analysis and experimental evidence revealed that Wee1 phosphorylation at Ser642, but not increased expression, was observed in hypertrophic cardiac tissues from both mice and human patients. Knockdown, pharmacological inhibition, or mutational inactivation of Wee1 significantly alleviated Ang II-induced cardiomyocyte injuries. RNA-seq analysis showed that phosphoinositide 3-kinases/protein kinase B (AKT) pathway mediated the function of Wee1 in cardiomyocytes. Mechanistically, the phosphorylated Wee1 directly binds to the PHD domain of AKT to phosphorylate AKT inducing AKT/phosphoinositide 3-kinases-nuclear factor κB signalling pathway activation and subsequent inflammation and hypertrophy in cardiomyocytes. Cardiomyocyte-specific Wee1 deficiency was found to protect against cardiac inflammation, remodelling, and dysfunction in mice subjected to transverse aortic constriction or Ang II infusion. Pharmacological Wee1 inhibition also attenuated Ang II-induced cardiac remodelling in mice. CONCLUSIONS:Cardiomyocyte Wee1 activation drives inflammation and hypertrophy by directly phosphorylating AKT and activating AKT-nuclear factor κB pathway. This study identifies Wee1 as a new upstream kinase of AKT and a potential therapeutic target for hypertensive heart failure.

Background:Although inflammatory cytokines are pivotal to the pathogenesis of sepsis, determining their causal roles remains challenging due to confounding biases. We employed Mendelian randomization (MR) to investigate genetically determined cytokine levels in sepsis risk, with translational validation in clinical cohorts and experimental models. Methods:A multi-omics framework integrated cis-protein quantitative trait loci (cis-pQTL) of plasma cytokines with the UK Biobank sepsis GWAS using inverse-variance weighted MR and Wald ratio methods. Sensitivity analyses, Bayesian co-localization analysis, phenotype scanning, and bidirectional MR ensured robustness. Clinical validation compared peripheral levels of the result found by MR analysis in severe sepsis patients (n = 15) and non-septic ICU controls (n = 11) within 24 hours of diagnosis. The temporal dynamics were further characterized in the cecal ligation and puncture (CLP) rat model, assessing blood and lung protein and mRNA levels of the result found in MR analysis at 24 hours to 120 hours, along with T-cell exhaustion markers. Results:Genetically elevated levels of CCL4 (Chemokine CC motif ligand 4) were associated with critical sepsis risk (OR = 0.70, 95% CI: 0.58-0.84, P = 1.45×10-4, FDR = 0.017), consistent across sensitivity analyses. Clinically, septic patients exhibited higher peripheral blood levels of CCL4 within 24 hours than controls. In the CLP rat model, peripheral and pulmonary CCL4 protein levels peaked at 24 hours but declined significantly by 120 hours. This decline was accompanied by transcriptomic evidence of T-cell exhaustion, with increased CTLA-4 and decreased IL-2 and IFN-γ. Conclusion:The trajectory of CCL4 follows distinct phases in sepsis-its early elevation is associated with hyperinflammation, while its later decline correlates with T-cell exhaustion. Although causal mechanisms require further validation, our findings propose that monitoring CCL4 dynamics may serve as a potential biomarker for immunophenotype stratification, highlighting its relevance for developing time-sensitive therapeutic strategies.

Perfluorooctane sulfonate (PFOS), a pervasive and persistent environmental pollutant, has been epidemiologically linked to thyroid disorders, but its toxic effects on papillary thyroid carcinoma (PTC) remain unclear. This study provides the clinical evidence that PFOS accumulates at significantly higher levels in human PTC tumor tissues compared to adjacent normal tissues (p = 0.037), indicating tissue-specific bioaccumulation. To investigate its health impact, we modeled chronic environmental exposure by treating human PTC cells with low, environmentally relevant concentrations of PFOS (0.01, 0.05 μM). Chronic exposure markedly enhanced malignant phenotypes, including proliferation, migration, and invasion. Mechanistically, PFOS activated the PI3K/AKT/mTOR signaling pathway, which subsequently drove epithelial-mesenchymal transition (EMT), as evidenced by upregulation of β-catenin and SNAI1, and increased expression of matrix metalloproteinase (MMP-2 and MMP-9). These pro-tumor effects were partially reversed by the pharmacological inhibitor BEZ235, which targets PI3K/mTOR. In vivo validation using a mouse xenograft model confirmed that PFOS exposure promotes tumor growth and upregulates the same pathway and effector molecules. This study provides integrated clinical and experimental evidence that PFOS exposure at environmentally relevant concentrations promotes PTC progression by inducing PI3K/AKT/mTOR-mediated EMT and associated enzyme secretion. These findings offer crucial experimental insight into the toxic role of PFOS as an environmental contaminant in thyroid tumors and underscore the urgent need for enhanced environmental health risk assessment and regulatory action.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a global condition affecting approximately 30% of adults worldwide. Recent research has clarified the key role of the NLRP3 inflammasome in the pathogenesis of MASLD, particularly in liver fibrosis and lipid accumulation. This study aimed to screen natural products targeting the NLRP3 inflammasome and assess their protective effects on MASLD. METHODS:We screened an in-house natural product library to identify potential NLRP3 inhibitors by evaluating the effects of the candidates on inhibiting IL-1β release in bone marrow-derived macrophages (BMDMs) challenged with lipopolysaccharide (LPS) and palmitic acid (PA). The therapeutic effects of the potential candidate were determined in a high-fat diet-induced MASLD mouse model. RESULTS:1-O-acetylbritannilactone (ABL) was found to inhibit NLRP3 inflammasome activation and NLRP3-mediated pyroptosis in BMDMs. Mechanistically, ABL covalently targeted NLRP3 at the Cys669 residue in the NLRP3 NACHT domain, thereby disrupting inflammasome assembly by selectively impeding the formation of the NLRP3-NEK7 complex. In vitro studies show that ABL exhibited an excellent inhibitory effect on lipid metabolism and liver fibrosis by restraining NLRP3 inflammasome activity. CONCLUSIONS:The study found that ABL mitigates MASLD in mice by inhibiting NLRP3 inflammasome, suggesting that ABL is an effective therapy for MASLD.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and while immune checkpoint inhibitor (ICI) has transformed treatment, resistance remains a critical challenge. Beyond the T-cell-centric view, tumor-infiltrating B lymphocytes (TIL-Bs) and tertiary lymphoid structures (TLSs) have emerged as pivotal prognostic determinants; however, the mechanistic interplay within the B-cell-autoantibody axis remains underexplored. Unlike previous reviews that primarily catalogue B-cell abundance, this synthesis integrates emerging evidence from single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to dissect the spatiotemporal dynamics of B-cell subsets. We elucidate how the maturation status of TLSs dictates the functional plasticity of TIL-Bs, switching between anti-tumor effector phenotypes (e.g., antibody-secreting plasma cells) and pro-tumor regulatory roles (e.g., IL-10+ regulatory B cells). Furthermore, we systematically examine the dualistic role of autoantibodies-not merely as serological biomarkers but as active regulators of the tumor immune microenvironment (TIME) through complement activation and antibody-dependent cell-mediated cytotoxicity (ADCC). Finally, we highlight the clinical and translational implications of targeting this axis, proposing precision strategies such as B-cell-based vaccines and the modulation of TLS neogenesis to overcome ICIs resistance. This review provides a comprehensive roadmap for integrating B-cell biology into next-generation personalized immunotherapy for NSCLC.

BACKGROUND:Necrosis of distal flap tissue is often attributed to ischemic injury. Previous research has indicated that Bergapten (BeG), known for its anti-inflammatory and antioxidant activities, protects tissues from ischemic injury. This investigation aimed to ascertain the beneficial effects of BeG on ischemic flap survival and explore its underlying mechanisms. METHODS:To assess the survival of ischemic skin flaps, analyses of flap viability were conducted utilizing survival rate evaluations and laser Doppler blood flow (LDBF) detection. RNA sequencing was performed to clarify the underlying molecular processes involved. In addition, angiogenesis, oxidative stress (OS), pyroptosis, transcription factor EB (TFEB)-mediated autophagy, and adenosine AMP-activated protein kinase (AMPK)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin (CaN) signaling were assessed using molecular docking (MD), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR), Western blot (WB) assays, immunofluorescence, and dihydroethidium (DHE) staining. RESULTS:The improvement in flap viability due to BeG was associated with the stimulation of autophagy, reduction of OS, and inhibition of pyroptosis. Notably, BeG-mediated enhancement of autophagic flux and increased resistance to OS were crucial for alleviating pyroptosis in vascular endothelial cells (VECs). BeG promoted autophagy flux and reduced endothelial oxidative stress by activating TFEB in ischemic flaps. However, the therapeutic effects of BeG were abolished by adeno-associated virus (AAV)-mediated TFEB knockdown. Additionally, BeG regulated TFEB activity through the AMPK-TRPML1-CaN pathway. CONCLUSIONS:BeG enhences autophagy and alleviates OS through stimulation of the AMPK-TRPML1-CaN-TFEB signaling cascade, hence improving the survival of ischemic flaps and potentially offering significant clinical implications.

Inflammatory bowel disease(IBD),as a chronic and recurrent intestinal inflammatory disorder,has seen a continuous increase in global incidence,which urgently calls for the development of novel therapeutic strategies.Its pathogenesis is complex,involving multiple factors such as genetics,environment,abnormal immune responses,and dysbiosis of the intestinal microbiota.The current treatment strategies for IBD mainly focus on suppressing abnormal immune responses and controlling inflammation,but still face challenges such as high recurrence rates,numerous adverse drug reactions,and poor efficacy in some patients.TCM has a long history of treating IBD and offers unique advantages such as multi-target intervention,holistic regulation,and individualized treatment.Tripterygium wilfordii,a TCM,has the effects of dispelling wind and dampness,activating blood and removing stasis,clearing heat and detoxifying,and reducing swelling and relieving pain.Its active components(including T.wilfordii polycoride,triptolide,and celastrol)play significant roles in the treatment of IBD through multiple pathways such as anti-inflammation,immune regulation,protection of the intestinal barrier,and regulation of the intestinal microbiota.This article systematically reviews the therapeutic mechanisms and clinical research progress of T.wilfordii and its active ingredients in the treatment of IBD,with the aim of providing theoretical references for the clinical treatment and new drug development of IBD.

BACKGROUND:Diabetic cardiomyopathy (DCM) is characterized by chronic low-grade inflammation and metabolic disturbances, leading to progressive cardiac dysfunction. Lycorine (LY), a complex tetracyclic pyrrolo[de]phenanthridine alkaloid from the Amaryllidaceae family, has shown potential anti-inflammatory effects, but its role in DCM pathogenesis remains unexplored. PURPOSE:This study investigated the cardioprotective effect of LY in DCM and its underlying molecular mechanisms. METHODS:We employed both in vitro (high glucose/palmitic acid-treated cardiomyocytes) and in vivo (streptozotocin-induced diabetic mice) models to investigate LY's cardioprotective effects. Liquid chromatography-tandem mass spectrometry, molecular docking, surface plasmon resonance binding assay, cellular thermal shift assay, and RNA interference approaches were utilized to identify the key target and mechanistic pathways. RESULTS:In vitro and in vivo models of DCM revealed that LY significantly attenuated cardiac inflammation. Mechanistically, liquid chromatography-tandem mass spectrometry analysis revealed that LY targeted interleukin enhancer-binding factor 3 (ILF3), a critical regulator of inflammatory responses. Notably, surface plasmon resonance and cellular thermal shift assay data validated a direct interaction between LY and ILF3. By interacting with ILF3, LY enhanced nuclear factor erythroid 2-related factor 2-mediated anti-inflammatory responses while suppressing NF-κB-driven pro-inflammatory signaling, thereby restoring inflammatory homeostasis and reducing myocardial injury. Furthermore, ILF3 knockdown mimicked the protective effects of LY, and ILF3 activity was essential for LY's cardioprotective effects. CONCLUSION:These findings suggest that LY ameliorates DCM by modulating ILF3-dependent nuclear factor erythroid 2-related factor 2 and NF-κB crosstalk to restore inflammatory balance, suggesting its potential as a novel therapeutic agent for diabetic cardiovascular complications.

OBJECTIVE:To explore the survival benefits of beta-blockers in patients with sepsis-induced TnT-positive myocardial injury across different clinical subtypes and to analyze their potential mechanisms of action. METHODS:Based on the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, 1102 patients meeting sepsis-induced TnT-positive myocardial injury criteria were included. Unsupervised machine learning methods were used for clinical subtype clustering analysis, and multivariate Cox regression was employed to evaluate the impact of beta-blockers on 28-day and 90-day mortality. The mediating role of inflammatory cytokine interleukin-6 (IL-6) and procalcitonin (PCT) was also analyzed. RESULTS:Patients were classified into three subtypes: moderate organ dysfunction sepsis-induced TnT-positive myocardial injury, severe inflammatory high-injury sepsis-induced TnT-positive myocardial injury, mild compensatory stable sepsis-induced TnT-positive myocardial injury. Beta-blocker use was significantly associated with reduced all-cause mortality: in all subtypes, 28-day mortality risk was reduced by 81.3% [hazard ratio (HR) = 0.187], 76.6% (HR = 0.234), and 65.9% (HR = 0.341), respectively, and 90-day mortality risk was reduced by 74.2% (HR = 0.258), 65.1% (HR = 0.349), and 63.6% (HR = 0.364), respectively. Selective beta-1 receptor blockers demonstrated the most optimal effects. The mediating role of IL-6 and PCT was not significant on the 28-day mortality rate in patients receiving beta-blocker. CONCLUSION:Beta-blockers can significantly improve short-term and medium-term survival rates in patients with sepsis-induced TnT-positive myocardial injury across all subtypes, particularly selective beta-1 blockers.

BackgroundMitochondrial dysfunction contributes to Porphyromonas gingivalis (P. gingivalis)-impaired endothelial function. Given the critical role of the mitochondrial permeability transition pore (mPTP) in mitochondrial homeostasis, this study explored how P. gingivalis promotes dynamin-related protein 1 (Drp1)-dependent mPTP overactivation, leading to mitochondrial damage and endothelial dysfunction.Materials and methodsMitochondrial and endothelial functions were evaluated in P. gingivalis-infected human aortic endothelial cells (HAECs) and C57BL/6 mice. Western blotting, immunofluorescence, and co-immunoprecipitation were used to assess the mitochondrial dynamics and mPTP-related protein interactions. Aortic vasodilation and endothelial integrity were examined following treatment with the Drp1 inhibitor Mdivi-1 or mPTP inhibitor cyclosporin A (CsA).ResultsP. gingivalis infection induced significant mitochondrial fragmentation, excessive mPTP opening, and impaired endothelium-dependent vasorelaxation. These changes were associated with enhanced p-Drp1 and its translocation to mitochondria. Mechanistically, P. gingivalis promoted voltage-dependent anion channel 1 (VDAC1) oligomerization in the out membrane of mitochondrial via p-Drp1 activation, which in turn disrupted the VDAC1-hexokinase 2 (HK2) interaction, facilitating mPTP opening. Inhibition of Drp1 and mPTP opening significantly alleviated mitochondrial dysfunction and restored endothelial function both in vitro and in vivo.ConclusionP. gingivalis impairs endothelial function via Drp1-VDAC1-HK2-mediated mPTP overactivation, highlighting a potential therapeutic target against vascular injury in periodontal infection.