Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes. In the normal physiological condition, EndoMT plays a fundamental role in forming the cardiac valves of the developing heart. However, EndoMT contributes to the development of various cardiovascular diseases (CVD), such as atherosclerosis, valve diseases, fibrosis, and pulmonary arterial hypertension (PAH). Therefore, a deeper understanding of the cellular and molecular mechanisms underlying EndoMT in CVD should provide urgently needed insights into reversing this condition. This review summarizes a 30-year span of relevant literature, delineating the EndoMT process in particular, key signaling pathways, and the underlying regulatory networks involved in CVD.

Estrogen receptor–negative (ER-negative) breast cancer is thought to be more malignant and devastating than ER-positive breast cancer. ER-negative breast cancer exhibits elevated NF-κB activity, but how this abnormally high NF-κB activity is maintained is poorly understood. The importance of linear ubiquitination, which is generated by the linear ubiquitin chain assembly complex (LUBAC), is increasingly appreciated in NF-κB signaling, which regulates cell activation and death. Here, we showed that epsin proteins, a family of ubiquitin-binding endocytic adaptors, interacted with LUBAC via its ubiquitin-interacting motif and bound LUBAC’s bona fide substrate NEMO via its N-terminal homolog (ENTH) domain. Furthermore, epsins promoted NF-κB essential modulator (NEMO) linear ubiquitination and served as scaffolds for recruiting other components of the IκB kinase (IKK) complex, resulting in the heightened IKK activation and sustained NF-κB signaling essential for the development of ER-negative breast cancer. Heightened epsin levels in ER-negative human breast cancer are associated with poor relapse-free survival. We showed that transgenic and pharmacological approaches eliminating epsins potently impeded breast cancer development in both spontaneous and patient-derived xenograft breast cancer mouse models. Our findings established the pivotal role epsins played in promoting breast cancer. Thus, targeting epsins may represent a strategy to restrain NF-κB signaling and provide an important perspective into ER-negative breast cancer treatment.

Background: Overweight and obese females demonstrate a significantly increased risk of anovulatory infertility. This study aims to investigate whether depression score could mediate the association between a body shape index (ABSI) and infertility, especially in overweight and obese population. Methods: We included 5431 adult female Americans from the National Health and Nutrition Examination Survey (NHANES, 2013–2018) database. ABSI manifested the body shape using waist circumference, weight, and height. Infertility or fertility status was defined by interviewing female participants aged ≥ 18 through the reproductive health questionnaires. Depression symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9) with total scores between 0 and 27. To investigate the association of infertility with ABSI and other individual components, survey-weighted multivariable logistic regression was performed. Mediation analysis of PHQ-9 score was conducted to disentangle the pathways that link ABSI to infertility among the NHANES participants. Results: 596 (10.97%) females were categorized with having infertility among 5431 participants. Participants with infertility showed higher ABSI and PHQ-9 score, appearing greater population proportion with depression symptoms. In the multivariable logistic regression model, ABSI (adjusted odds ratio = 0.14, 95% CI: 0.04 to 0.50) and PHQ-9 (adjusted odds ratio = 1.04, 95% CI: 1.01 to 1.07) were positively associated with infertility. PHQ-9 score was estimated to mediate 0.2% (P = 0.03) of the link between ABSI and infertility in all individuals, but to mediate 13.5% (P < 0.01) of the ABSI-infertility association in overweight and obese adult females. Conclusion: The association between ABSI and infertility seems to be mediated by depression symptoms scored by PHQ-9, especially in those adult females with overweigh and obesity. Future studies should be implemented to further explore this mediator in ABSI-infertility link.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-laden foam cells and plaques within the arterial wall. Dysfunctional vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells, and macrophages contribute to disease progression. Here, we report that macrophage-specific expression of epsins, highly conserved endocytic adaptor proteins involved in clathrin-mediated endocytosis, accelerates atherosclerosis in Western diet–fed mice. METHODS: WT/Apoe ^−/− (wild-type/Apoe-deficient) mice and littermates with a LysM-DKO/Apoe ^−/− (myeloid-specific deletion of epsin 1/2 on an Apoe ^−/− background) were generated and fed a Western diet for 16 weeks. Single-cell RNA sequencing was conducted to investigate the cellular and molecular mechanisms regulated by macrophage epsins during atherosclerosis. Findings from single-cell RNA sequencing were validated through metabolic profiling, qRT-PCR (quantitative reverse transcription polymerase chain reaction), immunostaining, and coculture experiments to assess associated phenotypic changes. RESULTS: LysM-DKO/Apoe ^−/− mice exhibited significantly reduced atherosclerotic foam cell formation compared with WT/Apoe ^−/− controls. Single-cell RNA sequencing analysis identified 19 major cell types, including 6 VSMC and 5 macrophage subpopulations. Modulated VSMC1 and VSMC2 subtypes were associated with inflammation, migration, and VSMC-to-macrophage transition. These populations, along with foamy-Trem2 and inflammatory macrophages, were markedly reduced in LysM-DKO/Apoe ^−/− mice. Transition of modulated VSMC2 subtype into macrophages was significantly inhibited, as confirmed by both computational analysis and experimental validation. In addition, macrophage epsin deletion reversed endothelial dysfunction, suppressed cholesterol- and glucose-mediated signaling, and reduced expression of proinflammatory ligands IL (interleukin)-1β and TNF-α (tumor necrosis factor α). CONCLUSIONS: Macrophage epsin deletion limits foam cell formation and preserves VSMC and endothelial cell phenotypes and functions. These findings reveal a potential therapeutic strategy targeting macrophage epsins to combat atherosclerosis.

Atherosclerosis is a chronic, multifactorial vascular disease and the leading global cause of cardiovascular morbidity. Its development reflects interconnected disturbances in lipid metabolism, endothelial function, inflammation, smooth muscle cell (SMC) phenotypic switching, and extracellular matrix remodeling. Genetic predisposition, including monogenic disorders such as familial hypercholesterolemia and polygenic risk variants, modulates disease susceptibility by altering lipid homeostasis as well as inflammatory and thrombotic pathways. Epigenetic regulators and noncoding RNAs, such as histone modifications, microRNAs, and long noncoding RNAs, further shape gene expression and link environmental cues to vascular pathology. Endothelial injury promotes lipoprotein retention and oxidation, triggering monocyte recruitment and macrophage-driven foam cell formation, cytokine secretion, and necrotic core development. Persistent inflammation, macrophage heterogeneity, and SMC plasticity collectively drive plaque growth and destabilization. Emerging insights into immune cell metabolism, intracellular signaling networks, and novel regulatory RNAs are expanding therapeutic possibilities beyond lipid-lowering. Current and evolving treatments include statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, anti-inflammatory agents targeting interleukin-1 beta (IL-1β) or NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and advanced approaches such as gene editing, siRNA, and nanoparticle-based delivery. Integrating multi-omics, biomarker-guided therapy, and precision medicine promises improved risk stratification and next-generation targeted interventions. This review summarizes recent molecular advances and highlights translational opportunities for enhancing atherosclerosis prevention and treatment.

Metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2DM) are closely linked conditions that share common disturbances in metabolism, inflammation, and fibrotic processes. MASH is characterized by fat accumulation in the liver, hepatocyte damage, and progressive fibrosis, whereas T2DM involves insulin resistance and impaired beta-cell function. The coexistence of these disorders creates a liver and pancreas feedback loop, in which impaired hepatic insulin signaling worsens blood glucose control and high glucose levels further damage the liver. Key cellular contributors include hepatocytes, Kupffer cells, hepatic stellate cells, and pancreatic β-cells, while non-coding RNAs influence lipid metabolism and inflammation. Emerging therapies, including GLP1 receptor agonists, dual incretin agents, PPAR modulators, thyroid hormone receptor beta modulators, FXR agonists, and FGF analogues, along with lifestyle interventions, show promise in improving both liver and metabolic outcomes. Precision medicine approaches may further refine individualized treatment strategies.