Apoptosis最新文献

Emerging as a novel secreted protein, Meteorin-like (Metrnl) exhibits substantial sequence homology with Meteorin (Metrn). Although Metrnl was initially identified in the context of adipose tissue and metabolic regulation, accumulating evidence has demonstrated its widespread expression across multiple tissues, including the nervous system, barrier tissues, and skeletal muscle. Functionally, Metrnl exerts pleiotropic biological effects and has been implicated as an adipokine, an immunomodulatory factor, and a cytoprotective mediator. This review provides an overview of current knowledge regarding the tissue-specific actions of Metrnl and summarizes the major signaling pathways associated with its activity. The integral role of Metrnl across different systems in both health and disease states is further examined, with a focus on elucidating its pathological involvement in various human disorders.

In this study, we show that during digit development, the embryonic limb contains an abundant and widespread population of “resident macrophages” that precede the onset of interdigital cell death responsible for the separation of digit primordia. The use of cultures of interdigital mesoderm at different remodeling stages, and GFP+ transgenic embryos in which the distal part of the autopodium has been surgically replaced by a fragment with identical characteristics from wild-type embryos, indicate that “transient macrophages” are also recruited at the beginning of interdigital death. The expression of the Pu.1 gene in coincidence with the onset of interdigital death suggests that primary yolk-sac macrophages are later complemented by macrophages of hematopoietic origin. Q-PCR analysis revealed a predominant M2/anti-inflammatory gene signature in the interdigits during the whole remodeling process that correlated with an interdigital transcriptome including Csf1, Il-34, Igf1, Igfbp5, Tgfβ4 (Tgfβ1 in mammals), P75^NTR/ Tnfrsf16, Hgf, Vegfa, that presumably stabilizes the macrophage M2 phenotype. However, M1-proinflammatory genes, including Tnfα and Tlr4, are expressed at very low levels prior to the onset of cell death but become up-regulated at the end of tissue remodeling. Together, our findings support the existence of “Tissue-Resident” and “Passenger/Transitory” macrophage populations of distinct origin and molecular profile participating in tissue remodeling processes associated with embryonic morphogenesis.

Acquired resistance to 5-fluorouracil (5-FU) curtails the survival benefit of chemotherapy in colorectal cancer (CRC). We asked whether a discrete subset of cancer-associated fibroblasts (CAFs) drives this phenotype. Multi-omic profiling of 24 CRC cohorts identified 10 collagen genes linked to poor outcome and 5-FU resistance; single-cell RNA-seq localized them to specific CAFs. Cellular communication modelling, in vitro proliferation, migration, apoptosis, and drug-sensitivity assays, together with CRISPR/Cas9 and siRNA perturbations, xenografts, and immunochemical analyses, examined the functional relevance of COL8A1-positive fibroblasts (COL8A1⁺Fibs) and their downstream signalling pathways. COL8A1⁺Fibs were enriched in advanced tumors and preferentially interacted with 5-FU-resistant malignant cells. Conditioned media from COL8A1⁺Fibs accelerated CRC cell growth, invasion, and 5-FU tolerance, and activated an epithelial–mesenchymal transition (EMT) programme. Secreted COL8A1 engaged integrin-β1 (ITGB1) on tumor cells; silencing ITGB1 or COL8A1 abrogated EMT induction, reduced proliferation, and restored 5-FU sensitivity in vitro and in vivo. COL8A1⁺Fibs orchestrate 5-FU resistance in CRC via a COL8A1/ITGB1-mediated EMT axis. Disrupting this stromal–tumor crosstalk represents a promising therapeutic strategy to overcome chemoresistance.

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Caspase-1, a cysteinyl aspartate-specific protease central to inflammasome activation, acts as a master regulator of multiple programmed cell death (PCD) pathways including pyroptosis, apoptosis, necroptosis, ferroptosis, and PANoptosis. It interacts with other caspases and is tightly modulated by epigenetic mechanisms and post-translational modifications. During the tumor microenvironment and immune metabolic regulation, it is activated and acts in a context-dependent way. Given this multifaceted involvement in cancer, neurodegenerative diseases and autoimmune disorders, caspase-1 represents a promising yet challenging therapeutic target. Despite extensive research, challenges persist in the insufficient understanding of crossover mechanisms and research of caspase-1 inhibitors. This review systematically clarifies its paradoxical roles by integrating caspase-1’ s regulatory and context-dependent networks across PCD, epigenetics, tumor microenvironment, immune metabolism, and diverse diseases. Additionally, we summarize therapeutic progress and root causes of caspase-1 inhibitors’ clinical failure as well as putting forward some innovative treatment strategies, aiming to offer new perspectives for future treating design.

Mitochondria, as essential organelles that integrate energy metabolism and intracellular signaling, have recently gained increasing attention in the study of pancreatic β-cell dysfunction in type 2 diabetes mellitus (T2DM). Programmed death of β-cells is recognized as a mechanism contributing to both disease progression and remission, primarily by impairing insulin secretion and disrupting glucose homeostasis. Accumulating evidence indicates that mitochondria serve as central hubs coordinating multiple programmed cell death (PCD) pathways. Structural or functional abnormalities of mitochondria initiate β-cell loss through distinct molecular mechanisms. This review systematically summarizes recent advances in understanding mitochondria-associated PCD in β-cells and its contribution to T2DM pathophysiology. Four major forms of PCD, including apoptosis, necroptosis, ferroptosis, and pyroptosis, are described in detail, highlighting their mitochondrial triggers and molecular signatures. Moreover, emerging mitochondrial-targeted therapeutic strategies are discussed, which aim to attenuate β-cell death and preserve functional mass. A better understanding of these processes may facilitate the development of novel therapeutic interventions to delay the onset and progression of T2DM and its related complications.

Primary solid tumors often exhibit accelerated glucose metabolism yet generate limited ATP due to reduced flux through the tricarboxylic acid (TCA) cycle. However, how these distinct metabolic alterations contribute to therapeutic resistance—and whether they represent targetable metabolic vulnerabilities—remains unclear. Here, we identify adenylate kinase 4 (AK4), a mitochondrial regulator of adenylate homeostasis, as a key mediator of radioresistance in glioblastoma (GBM) cells. We found that AK4 is upregulated in radioresistant GBM cells, where it suppresses mitochondrial oxidative phosphorylation to maintain redox homeostasis and promote cell survival following ionizing radiation (IR). Moreover, AK4 maintains elevated intracellular AMP, leading to the activation of AMP-activated protein kinase (AMPK), a master regulator of energy metabolism. AMPK activation subsequently inhibits acetyl-CoA carboxylase (ACC), suppressing cellular lipid synthesis. Through these mechanisms, AK4 limits IR-induced ferroptosis and contributes to radioresistance. Notably, we demonstrate that entinostat, a class I histone deacetylase (HDAC) inhibitor, downregulates AK4 expression and enhances the sensitivity of GBM cells to IR both in vitro and in vivo. In conclusion, our study reveals that AK4 promotes radioresistance in GBM by coordinating mitochondrial redox regulation and AMPK-mediated lipid metabolism, highlighting AK4 as a promising therapeutic target for overcoming GBM radioresistance.

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Colorectal cancer (CRC) has a high incidence and mortality rate worldwide, with chemotherapy being a cornerstone of treatment for locally advanced CRC patients (LACRC). Despite the relatively high efficacy of chemotherapy regimens like FOLFOX and CAPEOX, the resistance of chemotherapy remains a significant challenge. In this study, we identified sperm associated antigen 5 (SPAG5) as a potential therapeutic target in LACRC patients. High SPAG5 expression was correlated with improved progression-free survival (PFS) and overall survival (OS) in CRC patients receiving chemotherapy, as demonstrated by analyses of multiple cohorts, including TCGA, GEO and FUSCC. Mechanistically, SPAG5 overexpression promoted ferroptosis in CRC cells, enhancing chemotherapy efficacy through increased reactive oxygen species (ROS). SPAG5 depletion reduced ROS levels, attenuated ferroptosis, and decreased the cytotoxic effects of chemotherapy. These results indicate that SPAG5 can modulate ROS-dependent ferroptosis to enhance the chemotherapeutic response. Furthermore, inhibition of ROS reversed the chemotherapy-sensitizing effect mediated by SPAG5. Together, these findings suggest that SPAG5 may serve as a promising biomarker and therapeutic target to potentiate the cytotoxic effects of chemotherapy in LACRC patients.

The lung, a key organ for oxygen exchange, is particularly susceptible to high-altitude hypoxic stress. Hypoxia induces vascular impairment, which is characterized by vascular inflammatory responses and aging-like changes. Lipid metabolism has been shown to be closely associated with cellular homeostasis and membrane balance. However, the alterations in pulmonary lipid metabolism in response to high-altitude hypoxia are not fully characterized. In this study, model mice were subjected to a hypobaric chamber at an altitude of 5500 m for 3 days, and pulmonary microvascular endothelial cells (PMVECs) were cultured under 1% oxygen for 18 h to simulate the effects of acute severe hypoxia. High-altitude hypoxia significantly disrupted lung sphingolipid metabolism, accompanied by inflammation and aging-like changes in mice. Moreover, C24-Ceramide (Cer) and its synthase (CERS2) were significantly increased in PMVECs. C24-Cer was identified to bind to voltage-dependent anion channel 1 (VDAC1) (a mitochondrial outer membrane protein), which promoted mitochondrial DNA (mtDNA) release and subsequently induced the inflammation and aging-like changes by activating the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) pathway. Inhibition of C24-Cer or VDAC1 oligomerization by si-Cers2 or VBIT-4 could significantly reduce mtDNA release and alleviate inflammation and aging-like changes in the PMVECs and lung tissue under hypoxia. Our present work provides a novel and potential therapeutic target for high-altitude hypoxia-related vascular diseases.

Environmental pollutants have long been a major threat to human health, and long-term or high-concentration exposure can trigger acute or chronic diseases. These hazards often mediate tissue dysfunction and drive disease progression by inducing cell senescence and cell death (including apoptosis, pyroptosis, and ferroptosis). In recent years, the cGAS-STING signaling axis, as the core pathway for sensing cytosolic DNA, has received extensive attention and research. Its activation can promote the expression of type I interferons and inflammatory factors, playing an important role in immune defense such as anti-infection and anti-tumor. Notably, senescence-associated DNA leakage and mitochondrial dysfunction provide persistent ligands for cGAS, thereby establishing a self-sustaining cGAS-STING-driven inflammatory loop that exacerbates aging-related pathologies. However, research on the link between pollutants and the cGAS-STING pathway is still limited. In this review, we describe in detail the mechanism of action of the cGAS-STING pathway, focusing on how various pollutants (including heavy metals, air pollutants, and industrial chemicals) interfere with the cGAS-STING pathway, leading to cell damage and disease occurrence. Finally, we also list some drugs that can alleviate the impact of pollutants on the cGAS-STING signaling axis. Overall, this review aims to provide a theoretical basis for a deeper understanding of pollutant toxicity mechanisms and for developing intervention strategies targeting the cGAS-STING pathway.

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