Apoptosis最新文献

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.

The tumor microenvironment (TME) is a dynamic and complex biological system composed of cancer cells, stromal cells, fibroblasts, immune cells, extracellular matrix, and tumor vasculature. It plays a pivotal role in tumor initiation, progression, invasion, and metastasis, and therapeutic strategies targeting the TME have opened new avenues for tumor treatment and management. Within the TME, immune cells directly influence tumor development, while tumor cells evade immune surveillance through the regulation or silencing of key genes. Growing evidence suggests that cell death mechanisms are central to both tumorigenesis and immune evasion, providing targets for the development of diverse therapeutic strategies. This review explores the intricate relationship between various forms of cell death and immune escape in tumor cells, examining potential regulatory mechanisms of the TME in tumor progression from a micro perspective. Furthermore, it discusses the clinical applications of tumor immune escape and cell death mechanism-related targets and treatment strategies in antitumor immunity.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway serves as a core signaling axis for sensing cytosolic DNA and activating innate immunity. By recognizing abnormal DNA released from pathogens or tissue damage, it triggers the expression of type I interferons (IFN-I) and inflammatory cytokines, playing a pivotal role in innate immune defense, tumor immune surveillance, and tissue homeostasis regulation. As an important signaling hub in the fibroblast microenvironment, this pathway is involved in various pathophysiological processes such as antiviral immune responses, fibrosis progression, and remodeling of the tumor microenvironment (TME). In recent years, its potential in targeted therapy has become increasingly prominent: agonists of the pathway can enhance anti‑tumor immune responses, while inhibitors hold promise for alleviating aberrant inflammatory responses in fibrotic and autoimmune diseases. This review introduces the structural composition, signaling transduction process, and biological functions of the cGAS-STING pathway, and provides an overview of current research advances on related diseases, demonstrating the great potential of targeting this pathway in disease treatment.

Sepsis has a high morbidity and mortality rate, and effective therapeutic options remain limited. Lipopolysaccharide (LPS) is known to induce significant changes in the expression of forkhead box O (FOXO) transcription factor family members, and the mechanisms by which various drugs, including dexamethasone, treat sepsis are associated with the FOXO signaling pathway. Increased FOXO3 expression can reduce levels of inflammatory mediators, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), by more than one-third. However, FOXO proteins not only regulate inflammatory activity but also function as transcription factors with important roles across various tissues. The FOXO transcription factor family participates in cell-cycle regulation, apoptosis, autophagy, stress responses, DNA repair, tumorigenesis, and metabolism. Current research shows that FOXO proteins affect the occurrence, progression, and prognosis of sepsis by regulating several processes, including pro- and anti-inflammatory responses, immune regulation, oxidative stress, mitochondrial activity, vascular injury, and gut microbiota translocation. With improved understanding of FOXO-related mechanisms, researchers have proposed several strategies for therapeutic development targeting FOXO. These approaches include targeting upstream post-translational modifications, designing small-molecule agents that act on FOXO, regulating downstream proteins, and applying multi-target intervention strategies. These directions offer new possibilities for sepsis treatment.

Colorectal cancer (CRC) is a malignant tumor originating from the epithelial cells of the colon and rectum. Interleukin enhancer binding factor 2 (ILF2), an emerging RNA-binding protein, has been implicated in the regulation of multiple cancer-related processes. However, its specific role in the pathogenesis and progression of CRC remains largely unexplored. In this study, we systematically investigated the functional role of ILF2 in CRC through multi-level experiments. ILF2 expression was first assessed in clinical CRC tissues via quantitative real-time PCR and western blot. Functional implications were further examined through gain-of-function and loss-of-function approaches. Cellular assays included CCK-8 proliferation, colony formation, Transwell migration/invasion, macrophage coculture, and flow cytometry for apoptosis, complemented by immunofluorescence staining. In vivo relevance was confirmed using xenograft models for tumor growth and metastasis. Mechanistically, Co-IP revealed a robust interaction between ILF2 and ILF3, while RIP, RNA pull-down and dual-luciferase reporter assays demonstrated direct binding of ILF3 to KLF16 mRNA, suggesting a novel regulatory axis in CRC progression. Our results demonstrated that both ILF2 mRNA and protein were significantly upregulated in colorectal cancer (CRC) tissues compared to matched peritumoral tissues. Functional assays revealed that ILF2 overexpression enhanced, whereas ILF2 knockdown suppressed, the proliferation, migration, and invasion capabilities of CRC cells in vitro. Additionally, ILF2 overexpression induced M0 macrophages to polarize toward an M2-like phenotype. Consistent with these findings, in vivo experiments indicated that ILF2 facilitated tumor growth and promoted liver metastasis in CRC. Our work suggests that ILF2 formed a complex with ILF3 to enhance the stability of KLF16 mRNA, thereby contributing to CRC progression through the regulation of KLF16.

Graphical abstract

A proposed working model of the ILF2/ILF3/KLF16/β-catenin axis in colorectal cancer progression. Hypothetical model illustrating that ILF2 binding to ILF3 stabilizes KLF16 mRNA, which in turn activates β-catenin signaling. This pathway ultimately promotes CRC cell proliferation, invasion, liver metastasis, and M2-type macrophage polarization.

Background

Endometrial Cancer (EC) is one of the most prevalent malignancies in the female reproductive system. Hypoxia is a hallmark of the tumor microenvironment that drives metabolic reprogramming, endoplasmic reticulum (ER) stress, and aggressive behavior in cancer cells. However, the underlying mechanisms remain incompletely understood. This study aimed to investigate hypoxia-mediated regulation of EC progression, focusing on the role of SLC9A7 (Solute Carrier Family 9 Member A7, NHE7).

Methods

EC cells were exposed to hypoxic conditions (1% O₂) to assess phenotypic changes. Transcriptomic analysis, RT-qPCR, and western blotting were utilized to identify hypoxia-induced targets. Functional assays (proliferation, migration, invasion, tumor spheroid formation) and a xenograft mouse model were performed to evaluate NHE7’s roles. Bioinformatics analysis, pharmacological interventions (4-PBA, Ceapin-A7, 2-DG, Sodium oxamate), and chromatin immunoprecipitation (ChIP) were used to dissect molecular mechanisms.

Results

Hypoxia promoted the malignant phenotypes and stemness of EC cells. NHE7 was identified as a potential target gene of the hypoxia pathway and was positively correlated with poor prognosis in EC. Furthermore, overexpression of NHE7 in xenografts accelerated tumor growth. Mechanistically, NHE7 enhanced oxidative phosphorylation (OXPHOS) by elevating COX6C (Cytochrome C Oxidase Subunit 6C) expression, further driving ER stress. Hypoxia-driven glycolysis elevated histone lactylation, which transcriptionally activated NHE7. This regulation was reversed by glycolysis or lactate production inhibitors.

Conclusion

Hypoxia-driven glycolysis induces histone lactylation, leading to the upregulation of NHE7 expression. This process enhances OXPHOS-induced ER stress by upregulating COX6C expression, ultimately contributing to the malignant progression of EC.

Graphical abstract

Glioblastoma is the most aggressive and most common grade 4 tumor of the central nervous system (CNS). Despite standard treatments such as surgical resection and chemoradiotherapy, overall survival (OS) usually does not exceed 14–16 months in clinical trials, and no improvement in OS has been demonstrated even with the use of vascular endothelial growth factor A (VEGFA) inhibitors such as bevacizumab. In response to radiotherapy, hypoxia-inducible factor (HIF) stabilization leads to activation of alternative pro-angiogenic pathways, increasing VEGF expression and tumor angiogenesis. Several clinical trials evaluating HIF-2α inhibitors as monotherapy in the absence of concurrent VEGF inhibition, have similarly failed to demonstrate a significant improvement in OS outcomes. This review provides a perspective on the combined use of VEGF and HIF inhibitors, and provides an insight into future studies.

Neutrophil extracellular traps (NETs) drive severe acute pancreatitis (SAP) progression by promoting pancreatic injury, duct obstruction, and systemic inflammation. Reactive oxygen species (ROS) are critical for NETs formation, while NETs degradation remains therapeutically challenging. This study investigates whether combined N-acetylcysteine (NAC) and deoxyribonuclease I (DNase I) therapy mitigates SAP and associated lung injury by suppressing NETs formation and degradation, respectively, and explores the underlying molecular mechanisms. NETs were elevated in SAP pancreatic tissue. In vitro, NAC reduced NETs formation by inhibiting oxidative stress, while DNase I degraded preformed NETs. Combined therapy surpassed monotherapy efficacy, synergistically attenuating NETs burden. In vivo, Early dual intervention degraded NETs, reduced neutrophil infiltration and apoptosis, and lowered inflammatory cytokines, thereby alleviating pancreatitis and lung injury. Mechanistically, dual therapy suppressed NF-κB activation in pancreatic tissue, decreasing CXCL3 release and subsequent CXCR2-positive neutrophil recruitment, ultimately ameliorating SAP. NAC and DNase I synergistically target NETs generation and clearance, offering a promising redox-based therapeutic strategy for SAP.

Graphical abstract

This schematic diagram illustrates the in vivo mechanisms of combined NAC andDNase I administration in ameliorating SAP. Schematic Diagram of the Mechanism In Vivo, Created by BioRender.

The recent study by Gao et al. (Apoptosis, 2025. https://doi.org/10.1007/s10495-025-02194-x) proposes a compelling paradigm in which a positive feedback loop between glycolysis and nucleus pulposus cell pyroptosis acts as a central driver of intervertebral disc degeneration. Their work provides a crucial mechanistic link between dysregulated metabolism and inflammatory cell death, building upon long-standing observations of lactic acid accumulation and cellular demise in the degenerative disc. While this refined model represents a significant conceptual advance, our commentary identifies several layers of complexity that must be addressed for therapeutic translation. We argue that the proposed cycle operates within a highly specific pathophysiological context, with key concerns including the model’s applicability across the disc’s spatial heterogeneities, potential pathway redundancy upon therapeutic inhibition, and unresolved upstream instigators of the glycolytic shift. Future research must move beyond in vitro models to focus on spatially resolved mapping in human specimens, combinatorial therapeutic strategies, and elucidating the prime movers—mechanical, age-related, or senescent in origin—that initiate this vicious cycle.