Diabetic cardiomyopathy (DCM) involves metabolic dysfunction and adverse myocardial remodeling that can progress to heart failure. Ubiquitination links diabetic stress to changes in protein turnover, signaling-complex assembly, and organellar quality control. This review examines these mechanisms across cardiomyocytes, cardiac fibroblasts, endothelial cells, and immune cells, distinguishing direct DCM evidence from findings in other disease models. We compare E3 ubiquitin ligases and deubiquitinating enzymes that converge on lipid metabolism, mitochondrial function, inflammation, and regulated cell death. Their effects depend on substrate identity, ubiquitin-chain topology, cellular context, and interactions with other post-translational modifications. We also assess pharmacological modulation, cardiac-directed gene delivery, and targeted protein degradation, while identifying limitations in selectivity, safety, and human validation. Substrate-resolved and cell-specific studies are needed to determine which ubiquitination pathways can be targeted without disrupting essential cardiac proteostasis.
Cancer remains a major cause of morbidity and mortality worldwide, with its incidence and mortality rates continuing to rise. The long noncoding RNA SNHG4, a member of the small nucleolar RNA host gene family, has emerged as a candidate regulator in human cancers. This review synthesizes the currently reported expression patterns and clinical significance of SNHG4 across various malignancies, including colorectal cancer, hepatocellular carcinoma, gastric cancer, glioblastoma, prostate cancer, and lung cancer. Particular attention is given to tissue-dependent expression reversals, differences in evidence strength, and unresolved translational barriers. Additionally, this review describes the molecular mechanisms through which SNHG4 modulates oncogenic processes, including promoting cancer cell proliferation, migration, invasion, and epithelial‒mesenchymal transition and inhibiting apoptosis and ferroptosis. In summary, this review highlights the vital role of SNHG4 in cancer biology and critically evaluates its potential diagnostic and prognostic value together with the barriers to developing SNHG4-directed therapies. Despite these promising findings, the current evidence is largely derived from retrospective studies and preclinical models. Further large-scale, prospective multicenter studies with standardized detection methods are critically needed to validate the translational potential of SNHG4 before it can be considered for clinical application.
Triple-negative breast cancer (TNBC) exhibits a particularly high degree of aggression, and traditional Chinese medicine has demonstrated encouraging outcomes in the treatment of TNBC. This study aimed to elucidate the mechanisms by which Qishen Shuangbai formula (QSF), consisting of eight herbs, inhibits TNBC progression. MDA-MB-231 and BT549 cells were subjected to treatment with QSF at different concentrations. After bioinformatics analysis, the influence of alpha-2 A adrenergic receptor (ADRA2A)-mediated PI3K/AKT signaling on TNBC cells was verified using lentiviruses and the pathway inhibitor LY294002. A xenograft tumor model was established in nude mice via subcutaneous injection of MDA-MB-231 cells that had or had not undergone lentiviral infection, followed by QSF gavage to evaluate tumor growth. QSF inhibits the proliferation, migration, and invasion of TNBC cells while enhancing their apoptosis concentration-dependently. In vivo, it suppressed TNBC tumor growth, enhanced apoptosis, and reduced Ki67 expression in tumor tissues. QSF promoted expression of ADRA2A in TNBC cells, and elevated ADRA2A expression inhibited activation of the PI3K/AKT signaling pathway. Downregulating ADRA2A weakened the antitumor activity of QSF in TNBC cells. Treatment with the PI3K/AKT signaling inhibitor LY294002 also reduced the proliferation, migration, and invasion capabilities of TNBC while increasing apoptosis in the presence of ADRA2A knockdown. This study provides evidence that the inhibition of TNBC progression by QSF is related to the ADRA2A-mediated PI3K/AKT signaling pathway, which may shed light on exploiting QSF as a novel therapeutic agent for TNBC.
Asthma is a highly heterogeneous chronic inflammatory airway disease whose pathophysiology is determined by a combination of genetic, environmental, and immune factors. As the largest interface between the host and the environment, airway epithelial cells serve not only as a physical barrier against exogenous stimuli but also as central cells in sensing environmental threats and initiating immune responses. Among their functions, the release of epithelial-derived alarmins is a key step in initiating type 2 inflammation. Under the long-term interaction of genetic susceptibility and environmental factors, persistent structural and functional alterations occur in the airway epithelium of asthma patients. These include disruption of the barrier integrity, skewed cell differentiation, aberrant repair programs, and dysregulated alarmin release. These alterations not only exacerbate airway inflammation but can also directly drive the process of airway remodeling through mechanisms such as epithelial-mesenchymal transition, ciliary dysfunction, mucus hypersecretion, and paracrine regulation of smooth muscle. Remodeling also involves biochemical and mechanical alterations, including dysregulated expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), increased extracellular matrix (ECM) stiffness, and enhanced collagen crosslinking. Given the central role of the airway epithelium in asthma pathogenesis, targeting its alarmins and related signaling pathways holds promise for providing precise intervention strategies for patients with specific endotypes. This article systematically reviews the structural and functional changes in the asthmatic airway epithelium, analyzes the intrinsic links between barrier dysfunction, alarmin release, and airway pathological changes, and summarizes recent advances in interventions targeting the airway epithelium, aiming to provide a new theoretical basis for the precise diagnosis and treatment of asthma.
m5C modification plays a vital role in the progression of human cancers, including breast cancer (BC), but the function of NOP2/Sun RNA methyltransferase 2 (NSUN2), an RNA m5C modification enzyme, remains largely unclear. qRT-PCR, western blot and IHC assays were carried out to determine the expression of NSUN2, poly (ADP-ribose) polymerase 1 (PARP9) and Y box binding protein 1 (YBX1). EdU, flow cytometry, transwell, tube formation and sphere formation assays were conducted to evaluate cell proliferation, apoptosis, invasion, angiogenesis and stemness, respectively. ELISA was performed to examine the concentrations of inflammatory factors. RIP and pull-down assays were used to verify the interaction between NSUN2/YBX1 and PARP9. Murine xenograft model was constructed to explore the functions of NSUN2 and PARP9 in tumor growth in vivo. PARP9 silencing suppressed the proliferation, invasion, angiogenesis, stemness and immune escape, and promoted apoptosis in BC cells in vitro. Mechanically, NSUN2 functioned as an m5C writer that catalyzed m5C modification of PARP9 mRNA, while YBX1 acted as an m5C reader that recognized the modified transcript and enhanced its stability, thereby elevating PARP9 expression in BC cells. YBX1 could elevate PARP9 expression in BC cells. Moreover, NSUN2 knockdown restrained the malignant behaviors of BC cells, with PARP9 overexpression restored the effects. In addition, NSUN2 knockdown blocked tumorigenesis in vivo by regulating PARP9 expression. NSUN2-mediated m5C modification stabilizes PARP9 mRNA and is associated with enhanced BC progression and immune escape. The results broadened our understanding of the pathogenic mechanism of BC.
