Apoptosis最新文献

Voltage-dependent anion channel 2 (VDAC2) is a pivotal β-barrel protein located in the mitochondrial outer membrane (MOM), playing a central role in metabolite transport, ion homeostasis, and the determination of cell fate. Compared to other isoforms in the same family, VDAC2 possesses unique structural features-including an N-terminal extension, an enrichment of cysteine residues, and a distinct β-barrel conformation-which underlie its non-redundant functional roles. Notably, VDAC2 acts as a "dual regulatory hub" in apoptosis: it suppresses apoptosis by directly binding and inhibiting BAK, while also being essential for BAX-mediated apoptosis, demonstrating marked context-dependency. Furthermore, VDAC2 is deeply involved in tumor progression through its regulation of metabolic reprogramming, reactive oxygen species (ROS) homeostasis, ferroptosis, and mitochondrial quality control. Dysregulation of VDAC2 expression is closely associated with prognosis in multiple cancers, highlighting its promise as a diagnostic and prognostic biomarker, as well as a therapeutic target. This review systematically consolidates current knowledge on VDAC2 in oncology, identifies limitations and challenges in existing research, and aims to offer strategic insights to guide future investigations.

Abdominal aortic aneurysm (AAA) progression is closely linked to inflammation and endothelial dysfunction. Our previous study has demonstrated that increased CD95 ligand (CD95L) and its downstream effector Caspase-8 in the aortic tissue, contributed to AAA by modulating inflammation. However, how the CD95L/Caspase-8 modulated aneurysmal inflammation remains poorly understood. This study investigates how CD95L/Caspase-8 signaling drives endothelial pyroptosis to exacerbate AAA. Using a CaCl₂-induced AAA murine model and primary mouse aortic endothelial cells (MAECs), we demonstrate that CD95L triggers endothelial pyroptosis, characterized by NLRP3 inflammasome activation, Gasdermin D N-terminal (GSDMD-N) cleavage, and Caspase-8/Caspase 1 activation. Electron microscopy confirmed pyroptotic morphology, while flow cytometry excluded apoptosis or necrosis. CD95L elevated IL-1β/IL-18 secretion, which was abolished by Caspase-8 siRNA or inhibitor Z-IETD-FMK. Mechanistically, CD95L suppressed Caspase-8 phosphorylation at Tyr380, enabling its activation of GSDMD-dependent pyroptosis. In vivo, CaCl₂-induced AAA mice exhibited aortic dilation, elastin degradation, and endothelial-specific pyroptosis, all attenuated by endothelial-targeted Caspase-8 knockdown via AAV9-shRNA. This intervention reduced NLRP3 and GSDMD-N expression while preserving vascular integrity. Similarly, SRC kinase activation mitigated pyroptosis markers and aortic damage. These findings establish CD95L as a key mediator of endothelial pyroptosis in AAA via Caspase-8 dephosphorylation and NLRP3/GSDMD-N activation. Targeting Caspase-8 or enhancing SRC activity represents a promising therapeutic strategy to curb AAA progression by preserving endothelial homeostasis.

Beige adipocytes play a key role in non-shivering thermogenesis. SEMA3E, a member of the class 3 semaphorin family, is involved in various pathological processes, but its role in adipocyte differentiation and thermogenesis remains unclear. Here, we found SEMA3E expression increased in inguinal white adipose tissue (iWAT) following cold exposure or β-adrenergic agonist CL316,243 stimulation. In vitro, loss- and gain-of-function experiments revealed that SEMA3E promoted beige adipocyte differentiation and enhanced thermogenic genes expression. In vivo, fat transplantation experiments indicated that SEMA3E promoted adipogenesis. Furthermore, adeno-associated virus (AAV)-mediated SEMA3E knockdown in iWAT impaired thermogenesis in mice exposed to cold or CL316,243. RNA-Seq analysis linked SEMA3E to mitochondrial oxidative phosphorylation, and its knockdown reduced mitochondrial respiration by downregulating respiratory chain components expression and lowering mitochondrial oxygen consumption rate. Mechanistically, gene set enrichment analysis suggested SEMA3E regulated beige adipocyte differentiation via the Wnt/β-catenin pathway. SEMA3E knockdown delayed β-catenin degradation, while inhibiting this pathway with IWR-1 rescued the suppressed differentiation and thermogenic genes expression. In conclusion, these findings highlight the crucial role of SEMA3E in beige adipocyte differentiation and thermogenesis.

Ferroptosis is a new regulated cell death process, independent of apoptosis, necroptosis, and pyroptosis, which offers a promising therapeutic opportunity characterised by iron-dependent lipid peroxidation and mitochondrial membrane condensation. This has the advantage of being able to bypass the caspase-independent mechanism, thus avoiding apoptosis resistance in heterogeneous and drug-refractory tumours. Sensitivity to ferroptosis varies with factors of iron metabolism, redox balance, general environmental cues like hypoxia, acidification, nutrition, and involvement of fibroblast-associated alterations in the microenvironment and the immunosuppressive niche. Nanocarrier-based technology, which involves iron delivery systems, GPX4 inhibitors, ROS-amplifying polymers, and dual or multi-responsive platforms, results in some form of selective induction into ferroptosis and avoids off-target toxicity. Possible therapeutic combinations with chemotherapy, radiotherapy, photodynamic therapy, and immunotherapy could improve the antitumor efficiency. Yet, despite preclinical promise, there are indeed challenges such as the absence of an in vivo standardised biomarker, biosafety concerns, and regulatory bottlenecks. Future directions will potentially include smart self-amplifying nanocarriers, AI-guided theranostic systems, and predictive biomarkers to strategically position ferroptosis as an oncologic precision strategy overcoming resistance, heterogeneity, and immune modulation.

Myocardial injury and adverse remodeling following acute myocardial infarction (MI) drive heart failure progression, in which cardiomyocyte pyroptosis plays a critical pathogenic role. Bone morphogenetic protein 7 (BMP7) exerts anti-fibrotic and anti-inflammatory effects; however, its role in regulating pyroptosis during post-infarction cardiac repair remains unclear. We found that plasma BMP7 levels were markedly reduced in patients with chronic MI, showing a positive association with left ventricular ejection fraction and a negative correlation with myocardial fibrosis quantified by late gadolinium enhancement cardiac magnetic resonance imaging. In a mouse MI model, cardiomyocyte-specific BMP7 overexpression or exogenous BMP7 supplementation preserved cardiac function, reduced infarct size, and attenuated fibrosis and pyroptosis, whereas pharmacological inhibition of BMP7 with DMH-1 aggravated myocardial dysfunction and fibrosis. In primary neonatal rat ventricular myocytes, hypoxia induced BMP7 downregulation with increased pyroptosis, which was reversed by recombinant BMP7, while siRNA-mediated BMP7 knockdown further promoted pyroptotic death. BMP7 also suppressed the transition of cardiac fibroblasts into myofibroblasts. Mechanistically, BMP7 suppressed NF-κB p65 nuclear translocation, thereby limiting NLRP3 inflammasome activation and reducing pyroptosis. These findings identify BMP7 as a cardioprotective factor mitigating myocardial injury and remodeling after MI through NF-κB/NLRP3 inhibition, suggesting BMP7 as a potential therapeutic target for preventing heart failure.

Schematic illustration of the protective role of BMP7 against post-myocardial infarction injury through inhibition of NF-κB/NLRP3-mediated cardiomyocyte pyroptosis and fibroblast activation