Xing-Dong Xiong

Objective: Endothelial cell senescence induces endothelial dysfunction, thereby contributing to atherosclerosis progression. Circular RNAs (circRNAs) play diverse roles in multiple physiological and pathological processes. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic RNAs and dynamically regulates RNA fate and function. However, the functions and therapeutic potential of m6A-modified circRNAs in endothelial cell senescence remain unknown. Approach and Results: m6A-modified circRNAs associated with endothelial cell senescence were screened by circRNA expression and m6A-circRNA microarray profiling of endothelial cells and mouse aortic intima. circEZH2 expression was validated in endothelial cells, vascular tissues, and human atherosclerotic plaques by RT-qPCR, and RNA fluorescence in situ hybridization. The role of circEZH2 in endothelial senescence and atherosclerosis was assessed in vitro and in vivo. RNA pull-down, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assays, and rescue experiments were used to define the underlying mechanism. We identified A novel m6A-modified circRNA, circEZH2, that was downregulated in the aged aortic intima and advanced plaques. CircEZH2 was stabilized by m6A reader IGF2BP2. Endothelial cell-specific overexpression of circEZH2 delayed senescence and suppressed atherosclerosis progression. At the cellular level, circEZH2 overexpression delayed senescence, decreased p53/p21 levels and increased angiogenic activity of endothelial cells, while circEZH2 knockdown exhibited the opposite effect. Mechanistically, circEZH2 functions as a scaffold to promote USP37-mediated deubiquitination, thereby stabilizing ZNF326. Moreover, endothelial cell-specific knockdown of ZNF326 counteracts the anti-senescent and anti-atherosclerotic effects mediated by circEZH2 overexpression. Conclusion: In summary, the present study identifies circEZH2 as a novel suppressor of endothelial cell senescence, highlighting its potential as a therapeutic target for age-related atherosclerosis.

Super-enhancer-associated long non-coding RNAs (lncRNAs) have been shown to play key roles in the occurrence and development of malignant tumors, including esophageal squamous cell carcinoma (ESCC), yet their precise molecular mechanisms remain elusive. ChIP-Seq, dual-luciferase reporter assays, HiChIP-Seq, and ChIP-qPCR were performed to investigate the transcriptional regulation mechanism of MIR205HG. The functions and downstream signal transduction mechanisms of MIR205HG in ESCC were explored by a series of in vitro and in vivo assays. Furthermore, comprehensive bioinformatics methods were used to analyze its correlation with ESCC patient survival. Here, we identified and characterized MIR205HG, a lncRNA driven by super-enhancer, as a crucial oncogene in ESCC. MIR205HG was up-regulated in SCCs and its high expression correlated with poor clinical outcomes. Both TP63 and KLF5, two important master transcription factors in ESCC, could simultaneously occupy the super-enhancer region at the MIR205HG locus to promote its transcription and overexpression. MIR205HG is essential for ESCC proliferation, migration, invasion, and the growth of xenograft tumors in vitro and in vivo. Mechanistically, MIR205HG directly bound PTBP3 and acted as a molecular scaffold to promote HIF-1α translation, leading to enhanced cellular glycolysis via up-regulating the expression of HK2 and LDHA. Moreover, survival and pseudotime analyses of ESCC scRNA-seq data revealed a significant positive correlation between MIR205HG/PTBP3 signaling and the stemness and malignancy of ESCC cells. Finally, we showed that specifically targeting MIR205HG-SE using a CRISPR interference method resulted in potent suppressive effects on ESCC malignant phenotypes. We identified a pivotal oncogenic super-enhancer-driven lncRNA, MIR205HG, which interacts with PTBP3 to promote glycolysis in ESCC. It may serve as a promising prognostic biomarker and therapeutic target for patients.

Non-small cell lung cancer (NSCLC) remains a leading cause of global mortality, necessitating novel therapies. This study investigated the therapeutic role

Rationale: Endothelial cell senescence leads to endothelial dysfunction, thereby promoting the progression of atherosclerosis. Super-enhancers are crucial epigenetic cis-regulatory elements whose extensive reprogramming drives aberrant transcription in human diseases. However, the underlying mechanisms by which super-enhancers regulate endothelial cell senescence remain unclear. This study reveals the effect of liquid-liquid phase separation (LLPS) mediated by super-enhancer-driven core transcription factor FOXP1 on endothelial cell senescence.

CircSirt1 can ameliorate neointimal hyperplasia and provide protection against atherosclerosis. Single nucleotide polymorphisms (SNPs) in circRNA flanking

The dysfunction of endothelial cells (ECs) plays an essential role in the pathogenesis and development of a wide range of complex human diseases. These cells are important for regulating the functions of capillaries. Alterations in the vascular endothelium are associated with a broad spectrum of diseases, including atherosclerosis, stroke, hypertension, diabetes, coronary artery disease (CAD), venous thrombosis, cancer, and related angiogenesis disorders. Consequently, impaired endothelial function is recognized as a characteristic feature of numerous human diseases. circular RNAs (circRNAs) have recently expanded recognition as critical contributors to cellular processes, and their potential implications in endothelial dysfunction-related diseases have gained interest. While studies have extensively explored the roles of non-coding RNAs in endothelial dysfunction-related disease, the understanding of circRNAs in this context remains unclear. In this review, we aim to shed light on the mechanisms of circRNAs and their effect on endothelial dysfunction-related diseases. The investigation of circRNAs in endothelial dysfunction-related diseases such as atherosclerosis, hypertension, diabetes, and CAD holds great promises for uncovering innovative insights into disease pathogenesis and developing novel therapeutic approaches.

Senescence of vascular endothelial cells leads to endothelial dysfunction and exacerbates atherosclerosis. In this study, we presented evidence that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos) could delay endothelial cell senescence, promote endothelial cell proliferation, and enhance angiogenic activity in vitro. The miRNA profiling analysis revealed a high expression of miR-143-3p in hucMSC-Exos, which was further upregulated in endothelial cells treated with hucMSC-Exos. Silencing miR-143-3p induced endothelial cell senescence, as evidenced by increased senescence-associated β-galactosidase activity, reduced cell proliferation, and inhibited tubular formation; conversely, overexpression of miR-143-3p exhibited opposite effects. Moreover, we found that miR-143-3p directly targeted Cyclooxygenase-2 (COX-2) and suppressed its translation, thus delaying endothelial cell senescence. These results suggested that hucMSC-Exos can delay endothelial cell senescence by transferring miR-143-3p. In summary, our data demonstrated the potential of hucMSC-Exos as an intervention against vascular aging.

Activation of hypoxia signaling has been identified as an innate resistance signature against anti-PD-1 therapy, suggesting its potential as a target for combination treatments. Here, we demonstrate that UFMylation modification of HIF1α stabilizes the protein by antagonizing its ubiquitination and proteasomal degradation under hypoxic conditions. Mechanistically, depletion of UFL1 or defective UFMylation increases HIF1α binding to p53, promoting its degradation. Depletion of UFL1 or UBA5 , or defective UFMylation of HIF1α, destabilizes HIF1α, significantly inhibiting tumor growth and development in vitro and in xenograft mouse models. Defective UFMylation of HIF1α enhances the response to anti-PD-1 therapy in xenograft models. Clinically, UBA5 expression is upregulated in breast cancer tissues, and a selective UBA5 inhibitor reduces UFMylation activity and HIF1α protein levels, thereby enhancing anti-PD-1 combination therapy in mouse tumor models. Our findings highlight UFMylation as a critical posttranslational modification for the HIF1α pathway and a promising therapeutic target in hypoxic tumors.