Cell Death & Disease最新文献

Glioblastoma (GBM) acquires malignant traits through complex molecular adaptations that sustain immune evasion, often characterized by hypoxia and overexpression of the phagocytosis checkpoint CD47. However, the role of hypoxic drivers coordinating CD47-dependent immune evasion remains poorly defined. Here, we integrated single cell RNA sequencing and proteomic analysis to identify that insulin-like growth factor binding protein 2 (IGFBP2) was co-expressed with CD47 in hypoxic mesenchymal-like GBM subpopulations, synergistically promoting tumor progression and immune evasion. Mechanically, hypoxia induced IGFBP2 expression via HIF-2α-mediated transcriptional activation and further increased IGFBP2-positive exosome secretion through HIF-1α-dependent RAB3A upregulation. Moreover, IGFBP2 was predominantly localized on the exosome surface via integrin α5β1 and activated integrin/FAK/STAT3 signaling to enhance CD47 expression and inhibit macrophage phagocytosis. Clinically, serum exosomal IGFBP2 levels correlated with tumor grade and could serve as a diagnostic biomarker. Importantly, combinatorial blockade of IGFBP2 and CD47 synergistically suppressed tumor growth and prolonged survival in orthotopic GBM models. Together, our findings uncovered the hypoxia-exosomal IGFBP2-CD47 axis in GBM immune evasion and provided a compelling rationale for combination therapy to improve immunotherapy efficacy in GBM.

Photoreceptors (PRs) are specialized light-sensitive cells responsible for vision, and their death is the primary cause of retinal degeneration and vision loss. Recent studies using cells such as HeLa and PC12 have demonstrated cellular recovery even from late stages of apoptosis. Here, we demonstrate for the first time that PR cells can recover from features of apoptosis following exposure to apoptotic stressors. Upon apoptotic stimuli (staurosporine or hypoxia), 661 W cells, a murine cone PR cell line, exhibited morphological and functional features of apoptosis, such as rounding and blebbing, caspase-3 activation, PARP cleavage, and phosphatidylserine externalization. These processes were reversed upon the alleviation of stress. We also observed that mitochondrial function is central to apoptotic recovery of photoreceptor cells, as evidenced by the restoration of intracellular ATP levels and reduction in mitochondrial reactive oxygen species (mROS). Mitophagy was demonstrated to play a crucial role in cell survival, with increased protein and mRNA expression of mitophagy markers during recovery from apoptosis. Furthermore, the modulation of mitophagy confirmed its protective role in the recovery phase, as its induction with MF-094 reduced apoptosis while its inhibition with Mdivi-1 exacerbated cell death. In vivo, we demonstrate the recovery of PRs from apoptosis using an experimental model of transient retinal detachment. Altogether, the findings of this study indicate that PR cells can recover from entry into the apoptotic cascade, and that mitophagy is essential for apoptotic recovery in these cells.

IF1 is the natural inhibitor of the mitochondrial ATP synthase during hydrolytic activity. It has been found to be overexpressed in many tumors, where it acts as a pro-oncogenic protein. During oxidative phosphorylation, IF1 binds to a novel site on the OSCP subunit of ATP synthase and promotes tumorigenesis by protecting cancer cells from permeability transition pore (PTP)-dependent apoptosis. In this work, honokiol, a biphenolic compound, showed binding affinity for two sites on the OSCP subunit, as predicted by molecular docking analysis. It was shown to be effective in disrupting the IF1-OSCP interaction and sensitizing cancer cells to apoptosis. In vivo, xenografts of zebrafish injected with IF1-expressing HeLa cells showed tumor development. The same xenografts, treated with honokiol, showed a significant reduction in tumor mass, similar to untreated fish injected with IF1 KO HeLa cells. In vitro, honokiol inhibits colony formation in soft agar of IF1-expressing HeLa cells by promoting the PTP opening and cell death, without any effect on cell proliferation. Interestingly, honokiol was shown to block metastasis in fish xenografts and migration in a wound healing assay, by promoting mitochondrial swelling in both control and IF1 KO cell lines, when cells are moving to close the scratch area. In conclusion, honokiol appears to be a promising anti-cancer compound, with pro-apoptotic properties through the displacement of IF1 from the OSCP subunit of ATP synthase, and anti-metastatic effects that are due to mitochondrial PTP opening.

Although hypoxia is a well-known key driver of metabolic reprogramming in endometrial cancer (EC), its role in lactate-mediated macrophage activation remains unclear. This study investigates whether hypoxia-mediated lactate metabolism reprogramming facilitated EC progression via macrophages. Our data demonstrated that hypoxia-inducible factor 1 subunit alpha (HIF1A) drives a lactate-regulated metabolic cascade, elevating glycolytic genes and monocarboxylate transporter 3 (MCT3) in EC cells to produce and export more lactate. This lactate is transported to macrophages by MCT1 to drive M2 macrophage polarization. Mechanistically, lactate induces lactylation of Histone 3 in the promoter of DNA methyltransferase 1 (DNMT1) gene and activates transcription in macrophages, leading to the silencing of NHE7 gene expression, a key regulator of intracellular pH. Critically, NHE7 downregulation drives M2 polarization and senescence through the mitogen-activated protein kinase (MAPK) pathway activation in macrophages, ultimately facilitating EC progression. In vivo, we successfully established a xenograft tumor model using Ishikawa cells, and the data further confirmed that NHE7-overexpressing macrophages effectively abrogate exogenous lactate-accelerated xenograft tumor growth, as well as its M2 polarization and senescence. These findings uncover that hypoxia-mediated lactate production and transmission promote tumor-macrophage crosstalk via the DNMT1-NHE7 axis and EC progression, which offers novel therapeutic targets for EC.

The acidic tumor microenvironment provides the energy that drives the development of malignant tumors. High concentrations of lactic acid and H⁺ are key features of the acidic tumor microenvironment, and lactylation has gradually been shown to play a significant role in tumor progression. The expression of solute carrier family 26 member 3 (SLC26A3) is closely related to the occurrence and development of colorectal cancer (CRC), but the specific molecular mechanisms remain unclear. We demonstrated that alterations in the acidic microenvironment and overexpression of SLC26A3 significantly inhibited CRC occurrence and progression in vivo. Our study indicates that SLC26A3 undergoes lactylation in the acidic tumor microenvironment, which decreases SLC26A3 stability and expression. SLC26A3 interacts with the RNA-binding proteins Hu antigen R (HuR) and CUG-binding protein 1 (CUGBP1). When SLC26A3 expression is reduced, its ability to bind to HuR/CUGBP1 is weakened. As a result, HuR and CUGBP1 more readily interact with a subset of oncogenic mRNAs, regulating their stability and influencing their expression, ultimately promoting malignant tumor progression. These findings highlight the role of SLC26A3 as a potential suppressor of CRC recurrence, drug resistance, and metastasis, providing new insights for improving the clinical treatment and prognosis of CRC.

Colorectal cancer (CRC) ranks among the most prevalent malignancies of the digestive system, with the intricate tumor immune microenvironment (TIME) emerging as a key determinant of poor prognosis. Cancer-associated fibroblasts (CAFs), a central constituent of the tumor microenvironment, critically influence tumorigenesis and progression by orchestrating immunosuppression through cytokine secretion and other mechanisms. This study investigates the multifaceted interplay between CAFs and the immune system to identify novel therapeutic targets and improve prognostic outcomes for CRC patients. Through comprehensive analyses of clinical samples and public database data, we identified elevated MFAP2 expression in both CRC tissues and fibroblasts. Mechanistically, we established that CAFs-derived MFAP2 interacts with integrin β8 (ITGB8) on cancer cell surfaces, activating the integrin-FAK-ERK1/2 signaling cascade to drive CRC progression. Furthermore, ERK1/2 phosphorylates and activates the transcription factor ETS2, which upregulates the expression of CYP27A1, an enzyme that modulates lipid metabolism and suppresses CD8⁺ T cell function via liver X receptor beta (LXRβ) signaling. These findings elucidate a novel MFAP2-ITGB8-FAK-ERK1/2-ETS2-CYP27A1-LXRβ signaling axis, significantly activated by CAFs-derived MFAP2 in both in vitro and in vivo models, contributing to immune exhaustion and tumor progression. This axis offers significant therapeutic and prognostic potential for CRC, providing critical insights into CAF-mediated immune modulation and paving the way for targeted immunotherapeutic strategies.

Retinal ganglion cell (RGC) degeneration is a hallmark of glaucoma and other optic neuropathies, yet the transcriptional mechanisms that drive stress-induced neuronal apoptosis remain incompletely understood. Here, we identify the developmental transcription factor PAX6 as an aberrantly sustained and stress-responsive regulator in mature retinal neurons. Upon NMDA-induced excitotoxic stress, PAX6 is phosphorylated by the neuronal stress kinase JNK3, without changes in total expression levels. In vitro kinase assays confirm direct phosphorylation of PAX6 by JNK3, while genetic ablation of JNK3 abolishes PAX6 activation. This phosphorylation enhances PAX6 chromatin binding and enables its co-recruitment with JNK3 to promoters of pro-apoptotic genes, including Bax and Gadd45a. Genome-wide ChIP-seq and transcriptomic analyses reveal that PAX6 and JNK3 form a transcriptional complex that drives apoptotic gene expression. In vivo, AAV-shRNA-mediated knockdown of either PAX6 or JNK3 significantly attenuates excitotoxic RGC death. These findings define a previously unrecognized transcriptional mechanism by which JNK3-mediated phosphorylation of persistently expressed PAX6 converts a developmental factor into a driver of neuronal apoptosis. More broadly, this study highlights how the dysregulation of developmental transcriptional programs in postmitotic neurons can contribute to neurodegeneration, offering new mechanistic insights into stress-induced neuronal loss in chronic neurodegenerative diseases.

Inherited myopathies are genetic disorders characterised by declining motor function due to progressive muscle weakening and wasting. Recently, pathogenic variants in PAX7, the master transcriptional regulator of muscle stem cells, have been associated with myopathies of variable severity, arguing for impaired satellite cell function as the main pathogenic driver. Here, we report the characterisation of two missense PAX7 variants in a patient with asymmetric, progressive muscle weakness affecting facial, upper and lower body muscles, and myopathic changes on muscle pathology. Despite this disorder closely phenocopying the clinical presentation of Facioscapulohumeral muscular dystrophy (FSHD), genetic, epigenetic and transcriptomic profiling indicated that FSHD was unlikely. However, exome sequencing revealed two heterozygous variants in PAX7: c.335 C > T, (p.Pro112Leu) and c.1328 G > A (p.Cys443Tyr). Modelling these PAX7 variants in human myoblasts resembled the transcriptomic findings found in the muscle biopsy from the patient. Specifically, these PAX7 variants caused upregulation of splicing factors, an increase in mitochondrial reactive oxygen species levels and reduced cell proliferation. The phenotypic cell changes caused by the PAX7 variants support a pathomechanism whereby diminished satellite cell function impairs muscle homoeostasis. Together, multimodal investigation suggests that these variants in PAX7 are likely causative of an FSHD-like autosomal recessive myopathy and expand the spectrum of neuromuscular disorders originating from impaired satellite cell function.