Background The triglyceride-glucose (TyG) index, a novel surrogate marker of insulin resistance, has been linked to various cardiovascular diseases. While its role in aortic aneurysm and dissection has been studied, its prognostic value in patients with aortic dissection (AD) remains unclear. Methods In this retrospective cohort study, we screened 16,859 patients who underwent aortic computed tomography angiography (CTA) for chest pain at Tongji Hospital from 2012 to 2020. After exclusions, 1,136 patients with confirmed AD and complete clinical data were analyzed. The primary endpoint was in-hospital all-cause mortality. We used multivariable Cox regression models combined with propensity score matching (PSM) analysis to assess the association between TyG index and mortality risk. Subgroup analyses were conducted by surgical status and patient characteristics. Results Among the 1,136 patients, 291 (25.6%) died during hospitalization. Higher TyG index quartiles were significantly associated with increased mortality. In full adjusted models, patients in the highest TyG quartile (Q4) had a 76.8% increased mortality risk compared to Q1 (HR=1.500, 95% CI: 1.066–2.111, P=0.020). Importantly, this association remained robust after additional adjustment for dissection type and surgical status. Restricted cubic spline (RCS) analysis showed a linear relationship between TyG index and in-hospital mortality. Conclusions Our findings identify the TyG index as an independent predictor of in-hospital mortality in AD patients, underscoring its potential value for clinical risk stratification and prognosis assessment.

Persistent inflammation derived from neutrophil activation drives delayed healing of diabetic wounds. Herein, a dissolvable alginate methacryloyl-based microneedle patch functionalized with polypeptide CFLFLFK-NH2-coupled manganese/zinc ion metal-organic framework (MnZn-MOF) loading enalaprilat (Ena) (TMZE@A-MN) is developed. Ena promotes neutrophil repolarization from pro-inflammatory N1 to anti-inflammatory N2 state by inhibiting nuclear factor (NF)-κB axis and activating Smad3 pathway, attributed to Ena-induced level elevation of taurine and subsequently STING signaling cascade suppression, thus causing macrophage phenotype switching and endothelial cell ferroptosis repression. Due to identifiable property of CFLFLFK-NH2 on neutrophil membrane receptors, the delivery system endows Ena with targeting inhibitory roles in neutrophil activation. In addition, MnZn-MOFs possess free radical-eliminating performance and can effectively combat the growth of methicillin-resistant Staphylococcus aureus and Escherichia coli. In vivo evaluation on diabetic murine and porcine wounds also demonstrates that the TMZE@A-MN accelerates wound healing process. Consequently, the targeted microneedle delivery system holds great promise for diabetic wound treatment.

Background Endothelial‐to‐mesenchymal transition (EndMT) is a key contributor to cardiac fibrosis, yet the role and underlying mechanisms of endothelial integrin β3 (ITGB3) activation in EndMT remain poorly understood. This study aims to explore the involvement of a novel ITGB3– CaMKIIα (calcium‐calmodulin–dependent protein kinase IIα)–CREB1 (cAMP‐responsive element binding protein) signaling axis in EndMT and to demonstrate that targeting endothelial ITGB3 mitigates pressure overload–induced heart failure (HF) by reducing cardiac fibrosis. Methods Endothelial‐cell–specific ITGB3 knockout mice were subjected to transverse aortic constriction to induce HF. Cardiac function, and the expression of EndMT‐associated genes were assessed to evaluate changes in cardiac remodeling. RNA sequencing and primary human endothelial cells and mouse cardiac microvascular endothelial cells were used to investigate downstream mechanisms. Additionally, the ITGB3‐specific inhibitor RGDfK was applied in the treatment of HF. Results The activation of ITGB3 was predominantly observed within endothelial cells. Endothelial cell–specific ITGB3 deletion attenuated cardiac dysfunction. Mechanistically, ITGB3 knockdown and CaMKII inhibition reduced CaMKII activation and subsequently lowered nuclear CREB1 phosphorylation levels. Reciprocally, the genetic overexpression of ITGB3 in endothelial cells increased EndMT by activating the CaMKIIα–CREB1 axis. These results were further substantiated by pharmacological studies with the ITGB3 specific cyclic‐RGD (Arg‐Gly‐Asp) peptide inhibitor (RGDfK). RGDfK treatment ameliorated pressure overload–induced cardiac remodeling and markedly improved cardiac function, establishing the disease‐specific role of ITGB3 in vivo. Conclusions This study demonstrates that endothelial ITGB3 regulates EndMT and contributes to the progression of pressure overload–induced HF, partly through the CaMKIIα–CREB1 signaling pathway. Targeting ITGB3 to inhibit EndMT may offer a promising therapeutic strategy for HF.

Background: Aortic dissection (AD) is a life-threatening vascular emergency with limited effective pharmacological treatments. Recent studies have identified Src homology 2 domain-containing transforming protein C1 (p66Shc) as a crucial mediator of oxidative stress, apoptosis, and inflammation in aortic cells, thereby contributing to cellular dysfunction and vascular remodeling implicated in AD development and progression. Despite its established role in promoting vascular dysfunction and remodeling, the protective potential of targeting p66Shc in AD remains unclear. Methods: We quantified activated protein C (aPC) levels in clinical plasma samples from control subjects and AD patients using enzyme-linked immunosorbent assay (ELISA). To evaluate changes in p66Shc expression, we analyzed aortic tissues by Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF) staining. An in vivo AD model was established in thrombomodulin (TM)-mutant ApoE-/- mice, which display impaired TM-dependent PC activation, and exogenous PC was administered to evaluate its therapeutic effect. In parallel, mechanistic studies were performed in human endothelial cells using WB, co-immunoprecipitation (Co-IP), dual-label IF staining, chromatin immunoprecipitation (ChIP), luciferase reporter assays, and mitochondrial functional analyses. Results: In this study, we demonstrate that aPC, a coagulation protease with known cytoprotective properties, downregulates p66Shc expression through epigenetic modifications. Additionally, aPC can modulate the expression of a cold shock protein Y-box-binding protein 1 (YB1), which acts as a transcription factor, leading to elevated O-linked N-acetylglucosamine transferase (OGT) levels. This upregulation enhances the O-glycosylation of p66Shc on its 29th tyrosine residue, preventing its mitochondrial translocation, preserving mitochondrial membrane potential, and reducing reactive oxygen species (ROS) production. Consequently, these molecular mechanisms inhibit the onset and progression of AD. Conclusions: aPC epigenetically represses p66Shc transcription and promotes its O-glycosylation at Thr29 via the YB-1/OGT axis, thereby inhibiting mitochondrial ROS production and preventing vascular injury.

In metabolic dysfunction-related steatohepatitis (MASH), ITGB3 promotes hepatic fibrosis via activating hepatic stellate cells, but whether it directly regulates hepatic lipid metabolism through membrane-scaffolding function and the underlying mechanisms remain unclear. Transcriptomic analyses of human and murine models of MASH revealed consistent upregulation of ITGB3 in hepatocytes. In mice, the hepatocyte-specific overexpression of ITGB3 exacerbates diet-induced obesity, insulin resistance, steatosis, and fibrosis, the deletion of ITGB3 alleviates these phenotypes. Additionally, the overexpression of DHHC5 reversed the hallmarks of MASH in ITGB3-deficient mice, confirming the central role of DHHC5 in this process. Mechanistically, ITGB3 is a novel "accelerator" that directly increases CD36-mediated fatty acid uptake by recruiting LYN, then modulating LYN protein stability, and triggering LYN proteasomal degradation. This degradation relieves LYN-mediated inhibition of DHHC5 and promotes ITGB3/DHHC5/CD36 complex formation, thereby enhancing DHHC5-dependent CD36 palmitoylation and subsequent CD36-mediated fatty acid uptake. Pharmacologic inhibition of ITGB3 using cyclic-RGDfk peptide improved serum lipid profiles and hepatic steatosis. This study uncovers a previously unrecognized mechanism by which ITGB3 acts as a driver of hepatic steatosis of hepatic steatosis. Targeted intervention against ITGB3 to modulate CD36-mediated lipid uptake may represent a novel therapeutic strategy for the treatment of MASH.

In this retrospective study of 251 pediatric patients with T cell acute lymphoblastic leukemia (T-ALL), chronic hepatitis B virus (HBV) infection with acute exacerbation (CHB-AE) was associated with significantly poorer outcomes. Compared to patients with HBV-negative, the CHB-AE cohort had markedly inferior 5-year event-free survival (13.24% vs. 80.58%) and overall survival. After using propensity score matching to balance baseline characteristics, the difference in event-free survival remained significant. Subgroup analyses consistently showed worse outcomes for patients with CHB-AE, particularly those with high-risk features such as elevated leukocyte counts or central nervous system involvement. The study identifies HBV coinfection as an independent adverse prognostic factor in pediatric T-ALL. These findings highlight the urgent need for prospective studies to investigate the underlying mechanisms and to develop novel therapeutic strategies for this high-risk patient subgroup.

Cardiovascular diseases (CVDs) remain a significant public health burden, characterized by escalating morbidity and mortality rates and demanding novel therapeutic approaches. Cold shock protein Y-box binding protein 1 (YB-1), a highly conserved RNA/DNA-binding protein, has emerged as a pivotal regulator in various pathophysiological processes, including CVDs. YB-1 exerts pleiotropic functions by modulating gene transcription, pre-mRNA splicing, mRNA translation, and stability. The expression and function of YB-1 are intricately regulated by its subcellular localization, post-translational modifications, upstream regulatory signals. YB-1 plays a multifaceted role in CVDs, influencing inflammation, oxidative stress, cell proliferation, apoptosis, phenotypic switching of smooth muscle cells, and mitochondrial dysfunction. However, the regulation of YB-1 expression and function in CVDs is complex and context-dependent, exhibiting divergent effects even in the same disease across different cell types or at disease stages. This review comprehensively explores the structure, regulation, and functional significance of YB-1 in CVDs. We delve into the transcriptional and translational control mechanisms of YB-1, as well as its post-translational modifications. Furthermore, we elucidate the upstream signaling pathways that influence YB-1 expression, with a particular emphasis on non-coding RNAs and specific upstream molecules. Finally, we systematically examine the role of YB-1 in CVDs, summarizing its expression patterns, regulatory mechanisms, and therapeutic potential as a promising target for novel therapeutic interventions. By providing a comprehensive overview of YB-1's involvement in CVDs, this review aims to stimulate further research and facilitate the development of targeted therapies to improve cardiovascular health.

Aortic dissection (AD) is a life-threatening vascular disease marked by severe inflammation and immune cell infiltration. While complement activation has been implicated, the specific roles of complement component 3 (C3) and its active fragment C3a in AD pathogenesis remain unclear. In our study, C3/C3a levels were determined in plasma and aortic tissues from AD patients and β-aminopropionitrile-induced AD mice. Despite unchanged C3 levels, plasma C3a was markedly elevated and deposited in the aortic wall. The origin of C3a was traced using bone marrow-derived macrophages, identifying macrophages as the predominant source. Transcriptomic profiling and expressional validation of C3a-stimulated vascular smooth muscle cells (VSMCs) identified chemokine (C-C motif) ligand 9 (CCL9) as a downstream effector. Functional assays demonstrated that C3a recruited macrophages through C3a receptor (C3aR) and induced phenotypic switching of VSMCs toward a synthetic, pro-inflammatory state with increased CCL9 secretion. CCL9, in turn, promoted macrophage recruitment and activation via C-C chemokine receptor type 1 (CCR1) and augmented C3 synthesis, establishing a self-perpetuating inflammatory circuit. The C3 cleavage inhibitor Compstatin analog CP40 with two additional lysines at the C-terminus (CP40KK) was tested in vivo, showing that pharmacological blockade of C3 activation attenuated C3a and CCL9 expression, reduced macrophage infiltration, preserved aortic wall integrity, and improved survival outcomes in AD mice. In conclusion, we identified a C3/C3a-CCL9 feedback loop as a key driver of AD progression. This study highlights VSMCs as active regulators of vascular inflammation and positions C3a and CCL9 as potential therapeutic targets for AD intervention.

AIMS:Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus and frequently progresses to heart failure. Although the deubiquitinase OTUB1 has demonstrated protective effects in DCM, the upstream regulatory mechanisms governing its expression and their influence on mitochondrial function remain unclear. METHODS:We used a short-term insulinopenic diabetic mouse model supplemented with exogenous protein C (PC) to investigate the role of activated protein C (aPC) in regulating OTUB1 during early-stage DCM. A thrombomodulin-mutant (TMPro/Pro) mouse model, which limits endogenous PC activation, was employed to assess long-term effects. Additionally, a microRNA miR-493-5p sponge was delivered via recombinant adeno-associated virus (rAAV) to evaluate the therapeutic potential of miR-493-5p inhibition. RESULTS:Exogenous PC supplementation preserved cardiac function and restored OTUB1 protein levels in early-stage DCM without affecting Otub1 mRNA expression. In contrast, TMPro/Pro mice exhibited exacerbated cardiac dysfunction and reduced OTUB1 protein abundance. Mechanistically, we identified miR-493-5p as a direct translational repressor of OTUB1, which was upregulated in diabetic hearts and downregulated by aPC through endothelial protein C receptor-protease-activated receptor 1 signaling. Both in vitro and in vivo experiments confirmed that miR-493-5p impairs OTUB1-mediated mitochondrial function, resulting in cardiomyocyte apoptosis. Inhibition of miR-493-5p via rAAV-sponge delivery restored OTUB1 levels, improved mitochondrial morphology, and significantly enhanced cardiac function in diabetic mice. CONCLUSION:Our findings identify the aPC/miR-493-5p/OTUB1 axis as a critical regulatory pathway in DCM pathogenesis. Targeting this axis may represent a promising therapeutic strategy for preserving mitochondrial integrity and preventing diabetic cardiac dysfunction.

In this retrospective study of 251 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients, chronic hepatitis B virus (HBV) infection with acute exacerbation (CHB-AE) was associated with significantly poorer outcomes. Compared to HBV-negative patients, the CHB-AE cohort had markedly inferior 5-year event-free survival (13.24% vs. 80.58%) and overall survival. After using propensity score matching to balance baseline characteristics, the difference in event-free survival remained significant. Subgroup analyses consistently showed worse outcomes for CHB-AE patients, particularly those with high-risk features like elevated leukocyte counts or central nervous system involvement. The study identifies HBV coinfection as an independent adverse prognostic factor in pediatric T-ALL. These findings highlight the urgent need for prospective studies to investigate the underlying mechanisms and to develop novel therapeutic strategies for this high-risk patient subgroup.

Aortic dissection (AD), a life-threatening cardiovascular emergency, continues to impose high mortality due to insufficient therapeutic options, as monotherapy targeting angiotensin II type 1 receptor (AT1R) demonstrates limited clinical efficacy. Utilizing single-cell RNA sequencing, we identified integrin β3 as a critical driver of AD progression, with expression levels positively correlated with disease severity. Histopathological validation in human AD specimens and a murine angiotensin II (AngII)-infusion model confirmed marked upregulation of integrin β3 activation. Pharmacological blockade of integrin β3 with Cyclo(-RGDfK) significantly attenuated aortic pathogenesis in vivo , reducing dissection incidence and aortic degeneration. Mechanistically, AngII-mediated AT1R activation induced formation of a receptor complex with integrin β3, triggering its conformational activation. Transcriptomic profiling revealed that activated integrin β3 potentiates vascular endothelial dysfunction by binding glycogen synthase kinase 3β (GSK3β), which stabilizes β-catenin via a non-canonical Wnt signaling axis. This pathway drives endothelial barrier disruption, hallmarks of aortic wall destabilization in AD. Our findings unveil a previously unrecognized synergy between AT1R and integrin β3, implicating aberrant Wnt/β-catenin signaling as a nexus of endothelial injury in AD pathogenesis. These results advocate for a paradigm-shifting dual-therapeutic strategy concurrently targeting AT1R and integrin β3 to restore vascular homeostasis, offering a mechanistically grounded approach to mitigate this lethal disease. This work bridges critical gaps in understanding AD pathophysiology and provides a transformative framework for precision therapeutics. ### Competing Interest Statement The authors have declared no competing interest.

Panvascular disease, defined by the systemic involvement of multiple vascular beds, poses a growing challenge to contemporary diagnostic and therapeutic paradigms. Despite organ-specific manifestations, these conditions share a convergent pathological basis driven by chronic low-grade inflammation, immune dysregulation, and maladaptive vascular remodeling. Within this immunovascular interface, complement C3 (C3) has emerged as a pivotal regulator. Positioned at the convergence of the classical, lectin, and alternative complement pathways, C3 integrates systemic immune cues with microenvironmental stimuli to orchestrate endothelial activation, smooth muscle cell phenotypic switching, immune cell recruitment, platelet activation, and fibroinflammatory remodeling. This review provides a comprehensive analysis of C3 biology, including its structural domains, activation cascades, and downstream effector functions. We examine the role of C3 across major vascular cell types, endothelial cells, vascular smooth muscle cells, innate and adaptive immune cells, platelets, and fibroblasts, highlighting how C3 signaling dynamically shapes both acute injury responses and chronic vascular adaptation. In disease-specific contexts, we delineate how C3 contributes to the pathogenesis of atherosclerosis, coronary artery disease, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, peripheral vascular disease, stroke, and autoimmune- associated vasculitides. Special emphasis is placed on the dual-phase roles of C3, such as its injuryexacerbating effects in the acute phase of stroke versus its reparative functions in neuroregeneration. Finally, we review emerging therapeutic strategies targeting C3, with a focus on compstatin-based inhibitors, their pharmacological profiles, clinical trial progress, and immunological safety considerations. Collectively, this review reframes C3 as a master orchestrator of panvascular pathology and a promising target for precision immunomodulation across vascular systems.

Diabetic cardiomyopathy (DbCM) is a chronic metabolic disorder with few effective treatment strategies. Our previous study demonstrated that activated protein C (aPC), a serine protease, exerts cytoprotective effects in DbCM. However, the mechanisms underlying its role in DbCM require further elucidation. We developed a type 1 diabetic mouse model using thrombomodulin gene point mutation mice (TMP/P) with reduced endogenous aPC generation and investigated the protective effects of aPC on DbCM through intraperitoneal injection of protein C (PC). Myocardial functions and structure were assessed by echocardiography and histology. Transcriptomic analysis and immunological evaluation were conducted to investigate the downstream targets. The anti-senescence role of aPC was reaffirmed by PC treatment in vivo and aPC intervention in cultured neonatal rat ventricular myocytes in vitro. Endogenous aPC levels were reduced and positively correlated with cardiac diastolic function in diabetic mice. Cardiomyocytes manifested a senescent phenotype in DbCM. With impaired aPC activation, TMP/P mice exhibited aggravated diabetes-induced cardiac dysfunction and cardiomyocyte senescence. Mechanistically, aPC alleviated cardiomyocyte senescence in DbCM by acting on PAR1/PAR3 receptors to restore the interaction between P85 and CaMKIIδ, thereby inhibiting CaMKIIδ phosphorylation and its nuclear translocation. In summary, our study highlights that aPC ameliorates cardiomyocyte senescence in DbCM via PAR1/PAR3-P85-CaMKIIδ axis.

BACKGROUND:Accurate molecular and clinical stratification of patients with central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) remains challenging, impeding the development of personalized therapeutic approaches. Herein, we investigated the translational significance of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) in pediatric NGGCTs to identify characteristic features of CNS NGGCTs and to identify a subset of patients for whom the presence of residual disease is a risk factor and an indicator of shorter progression-free survival (PFS) and overall survival (OS). METHODS:Medical records of patients with CNS NGGCTs between January 1, 2018 and December 31, 2022 were reviewed retrospectively. RESULTS:The cohort consisted of 11 male and six female patients. Tumor markers were elevated in four of the five people who underwent surgery. The remaining 12 patients were diagnosed with malignant NGGCTs according to elevated tumor markers. Among them, ctDNA before chemotherapy as well as ctDNA clearance were consistently associated with PFS and OS (p < .05). By setting a ctDNA positivity threshold of 6%, patients with high ctDNA (above the threshold) levels, which had limitation due to the selection based on optimal statistic from the survival analysis, had significantly inferior 5-year PFS and OS compared to those with low levels (below the threshold). ctDNA or ctDNA clearance combined with the presence of residual disease predicted significantly worse OS and PFS (p < .05). CONCLUSIONS:CSF ctDNA might allow the study of genomic evolution and the characterization of tumors in pediatric NGGCTs. CSF ctDNA analysis may facilitate the clinical management of pediatric NGGCT patients, and aid in designing personalized therapeutic strategies.

Background Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disease characterized by complement dependent and proinflammatory activation of macrophages. However, effective treatment for complement activation in PAH is lacking. We aimed to explore the effect and mechanism of CP40-KK (a newly identified analog of selective complement C3 inhibitor CP40) in the PAH model. Methods We used western blotting, immunohistochemistry, and immunofluorescence staining of lung tissues from the monocrotaline (MCT)-induced rat PAH model to study macrophage infiltration, NLPR3 inflammasome activation, and proinflammatory cytokines (IL-1β and IL-18) release. Surface plasmon resonance (SPR), ELISA, and CH50 assays were used to test the affinity between CP40-KK and rat/human complement C3. CP40-KK group rats only received CP40-KK (2 mg/kg) by subcutaneous injection at day 15 to day 28 continuously. Results C3a was significantly upregulated in the plasma of MCT-treated rats. SPR, ELISA, and CH50 assays revealed that CP40-KK displayed similar affinity binding to human and rat complement C3. Pharmacological inhibition of complement C3 cleavage (CP40-KK) could ameliorate MCT-induced NLRP3 inflammasome activity, pulmonary vascular remodeling, and right ventricular hypertrophy. Mechanistically, increased proliferation of pulmonary arterial smooth muscle cells is closely associated with macrophage infiltration, NLPR3 inflammasome activation, and proinflammatory cytokines (IL-1β and IL-18) release. Besides, C3a enhanced IL-1β activity in macrophages and promoted pulmonary arterial smooth muscle cell proliferation in vitro. Conclusion Our findings suggest that CP40-KK treatment was protective in the MCT-induced rat PAH model, which might serve as a therapeutic option for PAH.

In up to one-third of nonalcoholic fatty liver disease (NAFLD) patients, simple steatosis progresses to its more severe form, nonalcoholic steatohepatitis (NASH), but the precise mechanisms underlying this transition are not fully understood. Toll/interleukin-1 receptor 8 (TIR8), a conventional innate immune regulator highly expressed in hepatic tissue, has shown potential for ameliorating various inflammation-related disorders. However, its role in NASH pathogenesis, especially its regulatory effects on lipid metabolism and inflammatory responses, is still unclear. Here, using a TIR8 knockout (TIR8KO) mouse model and mass spectrometry analyses, we found that TIR8KO mice displayed aggravated hepatic steatosis and inflammation, whereas TIR8 overexpression attenuated these adverse effects. Ectopic TIR8 expression counteracts free fatty acid (FFA)-induced PPARα inhibition and downstream signaling. A decrease in TIR8 levels in hepatocytes heightened lipopolysaccharide (LPS) sensitivity. Notably, FFA stimulation led to a direct interaction between TIR8 and proteasome subunit alpha type 4 (PSMA4), facilitating TIR8 degradation. These results revealed that TIR8 safeguards PPARα-regulated lipid metabolism and mitigates inflammation induced by external factors during NASH progression. Our study highlights TIR8 as a promising target for NASH therapy, indicating the potential of TIR8 agonists in treatment strategies.

Histone demethylation is a key post-translational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Lysine specific demethylase 6A (KDM6A, also known as UTX) is an Fe2+- and α-ketoglutarate- dependent oxidase which belongs to KDM6 Jumonji histone demethylase subfamily, and it can remove mono-, di- and tri-methyl groups from methylated lysine 27 of histone H3 (H3K27me1/2/3). Mounting studies indicate that KDM6A is responsible for driving multiple human diseases, particularly cancers and pharmacological inhibition of KDM6A is an effective strategy to treat varieties of KDM6A-amplified cancers in cellulo and in vivo. Although there are several reviews on the roles of KDM6 subfamily in cancer development and therapy, all of them only simply introduce the roles of KDM6A in cancer without systematically summarizing the specific mechanisms of KDM6A in tumorigenesis, which greatly limits the advances on the understanding of roles KDM6A in varieties of cancers, discovering targeting selective KDM6A inhibitors, and exploring the adaptive profiles of KDM6A antagonists. Herein, we present the structure and functions of KDM6A, simply outline the functions of KDM6A in homeostasis and non-cancer diseases, summarize the role of KDM6A and its distinct target genes/ligand proteins in development of varieties of cancers, systematically classify KDM6A inhibitors, sum up the difficulties encountered in the research of KDM6A and the discovery of related drugs, and provide the corresponding solutions, which will contribute to understanding the roles of KDM6A in carcinogenesis and advancing the progression of KDM6A as a drug target in cancer therapy.

Diabetic cardiomyopathy (DCM) is a chronic metabolic disease with few effective therapeutic options. Immunoproteasome is an inducible proteasome that plays an important role in the regulation of many cardiovascular diseases, while its role in DCM remains under discussion. The present study aims to demonstrate whether inhibiting immunoproteasome subunit low molecular weight polypeptide 7 (LMP7) could alleviate DCM. Here, we established a type I diabetes mellitus mouse model by streptozotocin (STZ) in 8-week-old male wild-type C57BL/6J mice. We found that immunoproteasome subunit LMP7 was overexpressed in the heart of diabetic mice, while inhibiting LMP7 with pharmacological inhibitor ONX0914 significantly alleviated myocardial fibrosis and improved cardiac function. Besides, compared with diabetic mice, ONX0914 treatment reduced protein levels of mesenchymal markers (Vimentin, α-smooth muscle actin, and SM22α) and increased endothelial markers (VE-cadherin and CD31). In TGFβ1 stimulated HUVECs, we also observed that ONX0914 could inhibit endothelial-mesenchymal transition (EndMT). Mechanistically, we prove that ONX0914 could regulate autophagy activity both in vivo and vitro. Meanwhile, the protective effect of ONX0914 on TGFβ1 stimulated HUVECs could be abolished by 3-methyladenine (3MA) or hydroxychloroquine (CQ). All in all, our data highlight that inhibition of LMP7 with ONX0914 could ameliorate EndMT in diabetic mouse hearts at least in part via autophagy activation. Thus, LMP7 may be a potential therapeutic target for the DCM.