Cell Death Discovery最新文献

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder characterized by persistent mucosal immune activation and compromised epithelial barrier function. In this study, we identify the RNA-binding protein PUMILIO2 (Pum2) as a previously unrecognized regulator of intestinal inflammation. Analysis of colonic tissues from UC patients revealed reduced Pum2 expression, which inversely correlated with disease activity. In dextran sulfate sodium (DSS)-induced colitis models, Pum2 deficiency exacerbated mucosal injury, accompanied by heightened macrophage inflammation. Mechanistically, Pum2 loss during colitis drives macrophage hyperactivation and TNFα-dependent epithelial necroptosis, which together intensify pathogenic macrophage-epithelial interactions and barrier breakdown. The dynamic downregulation of Pum2 in active inflammation underscores its potential as a therapeutic target for modulating macrophage-epithelial interactions and restoring intestinal barrier integrity in the context of colitis.Abstract Figure. Pum2 deficiency aggravates colitis via macrophage-epithelial crosstalk driving inflammation and necroptosis. Left: Pum2 loss promotes macrophage-driven inflammation, with increased chemokine expression, macrophage infiltration, and a pro-inflammatory phenotype characterized by TNFα secretion. Right: Macrophage-epithelial crosstalk triggers epithelial necroptosis. Proinflammatory signals from Pum2-deficient macrophages sensitize epithelial cells to TNFα-induced death. Simultaneously, epithelial Pum2 loss elevates ROS, facilitating RIPK1, RIPK3, and MLKL phosphorylation. This synergistic cascade amplifies necroptosis and establishes a self-perpetuating loop of barrier disruption and inflammation.

The GBA1 gene encodes the enzyme glucocerebrosidase, which is responsible for lysosomal degradation of the glycosphingolipid glucosylceramide. Biallelic mutations in GBA1 are causative for Gaucher disease, whereas either monoallelic or biallelic mutations are a risk factor for Parkinson's disease. GBA1 mutations, beside reducing enzymatic activity and leading to substrate accumulation, influence a number of molecular and cellular pathways, including lipid homeostasis, endosome-lysosome pathway, endoplasmic reticulum to Golgi protein trafficking, autophagy and mitophagy. Given the critical role of GBA1 in these key pathways for cellular homeostasis, it can be expected that alterations in this enzyme may influence also cancer development and/or pathology, keeping in mind that Gaucher disease is associated with an increased risk of cancer development. Notably, a large fraction of patients affected by different cancer types carry an amplification of the long arm of chromosome 1, that includes the GBA1 gene. Furthermore, GBA1 expression is elevated in different cancer tissues, compared with healthy counterparts and associated with outcome in some cases. In this perspective, we narratively review the main evidence supporting a role for GBA1 in influencing tumorigenesis and we present our analyses on GBA1 amplification and expression throughout different cancer types. Taken together, these data suggest that the presence of a GBA1 germline mutation or a somatic amplification may influence cancer pathogenesis and/or response to therapies through context-dependent mechanisms that are still to be characterized.

Cleft palate, a prevalent congenital disorder, arises from dysregulated embryonic palatal fusion, but the posttranslational modifications (PTMs) driving this process remain poorly understood. Here, we report that lysine acetylation is a critical MSX1 proteostasis switch that governs embryonic palatal mesenchymal (EPM) cell survival. We demonstrate in vitro and in vivo that MSX1 protein stability regulation by deacetylase SIRT1-catalyzed acetylation underlies EPM apoptosis and palatal fusion. In atRA-induced cleft palate models, SIRT1 suppression drives MSX1 hyperacetylation, accelerating proteasomal degradation and culminating in EPM apoptosis. Strikingly, transcriptomic profiling revealed the exclusive proteostatic role of acetylation, indicating that MSX1's structural stability differs from its transcriptional activity-a paradigm distinct from that of classic PTM mechanisms during development. Lentivirus-mediated delivery of the deacetylase SIRT1 or the deacetylation mimic MSX1 K139R significantly reduced cleft severity, indicating its preventive and therapeutic potential in humans. Our work establishes the MSX1 acetylation as both a pathogenic driver and a druggable target in cleft palate, redefining PTM regulation as a central etiological factor in genetic disorders.

Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of the von Hippel-Lindau (VHL) gene, leading to constitutive activation of hypoxia-inducible transcription factors (HIFs) and metabolic reprogramming toward aerobic glycolysis. Although core fucosylation catalysed by fucosyltransferase 8 (FUT8) is known to regulate receptor signaling and tumor malignancy, its role in metabolic regulation of ccRCC remains poorly defined. Here, we demonstrate that FUT8 knockdown significantly suppresses ccRCC proliferation and migration both in vitro and in vivo. Mechanistically, FUT8 enhances HIF-1α-driven glycolysis, increasing lactate production and promoting pan-lysine lactylation (pan-Kla). Specifically, FUT8 promotes pyruvate kinase M2 (PKM2) K115 lactylation, which boosts its enzymatic activity while reducing nuclear localization, thereby driving epithelial-mesenchymal transition and malignant progression. Collectively, our findings reveal the FUT8-HIF-1α-lactate-PKM2 axis as a key mechanism that links core fucosylation to metabolic reprogramming and malignant progression in ccRCC and highlights FUT8 as a promising therapeutic target.

Resistance to cisplatin limits its clinical efficacy in LUAD patients and leads to poor prognosis. SERPINE1 mRNA binding protein 1 (SERBP1), an RNA-binding protein, is associated with tumorigenesis and progression. However, its specific role in cisplatin resistance and underlying mechanism in LUAD remain unclear. Here, we investigated the hypothesis that SERBP1 drives cisplatin resistance by reinforcing DNA damage repair capacity. We found that SERBP1 was consistently upregulated in cisplatin-resistant LUAD cells compared with cisplatin-sensitive counterparts. Gain-of-function and loss-of-function experiments demonstrated that SERBP1 promoted cisplatin resistance in LUAD. Mechanistically, SERBP1 contributes to cisplatin resistance by stabilizing BRCA1 mRNA, thus activating HR repair mediated by RAD51. Importantly, BRCA1 knockdown attenuated SERBP1-driven cisplatin resistance both in vitro and in vivo, establishing BRCA1 as a critical downstream effector of SERBP1. Collectively, these findings identify SERBP1 as a determinant of cisplatin resistance in LUAD and reveal a SERBP1-BRCA1 axis that promotes HR repair and chemoresistance, thereby highlighting SERBP1 as a potential therapeutic target to overcome cisplatin resistance.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degradation and a complex pathogenesis. Degenerated chondrocytes exhibit an imbalance between catabolism and anabolism, leading to cartilage matrix loss. Currently, there are no effective clinical therapies to halt or reverse this degeneration. This study investigated the therapeutic potential of Dapagliflozin (DAPA) for OA. We demonstrated that DAPA exerts protective effects on cartilage explants from patients with OA as well as in surgically induced OA models in mice. In vitro studies revealed that DAPA ameliorates OA by restoring chondrocyte metabolic homeostasis. Transcriptome sequencing showed that DAPA activated the AMP-activated protein kinase (AMPK) signaling pathway while suppressing MAPK signaling. Mechanistically, AMPKα was identified as a novel target of DAPA. DAPA alleviated excessive catabolism by targeting both AMPKα and SGLT2, while promoting anabolic processes through AMPKα activation. Furthermore, DAPA rescued impaired autophagy caused by SGLT2 upregulation in degenerated chondrocytes. Our findings demonstrated that DAPA regulates cartilage metabolism by concurrently modulating AMPKα and SGLT2, underscoring the therapeutic promise of combined AMPK activation and SGLT2 inhibition in OA treatment.Mechanism of DAPA in treating osteoarthritis. Created with BioRender.com.

Traumatic optic neuropathy (TON) occurs due to trauma to the optic nerve, resulting in blindness. Current management focuses primarily on supportive care, highlighting an urgent need to identify novel treatment targets. Neuronal expression of the enzyme histone deacetylase 3 (HDAC3) has been previously implicated in retinal ganglion cell (RGC) degeneration after optic nerve crush (ONC), a model of TON. Here we investigated the role of myeloid HDAC3 (i.e., HDAC3 expressed in microglia and macrophages) in RGC loss, axonal degeneration, and efferocytosis, a reparative process by which phagocytic myeloid cells engulf apoptotic cells. ONC injury was performed on myeloid-specific HDAC3 knockout (KO) and floxed control mice. Neurodegeneration and efferocytosis assays were assessed using retina flatmount immunolabeling and confocal imaging. RGC function was evaluated using pattern electroretinography (PERG). Axonal sprouting was quantified by anterograde transport of cholera toxin B injected intravitreally. Myelin debris clearance was assessed in optic nerves in vivo and in vitro using bone-marrow-derived macrophages isolated from myeloid HDAC3 KO and control mice. Myeloid HDAC3 deletion preserved RGC and improved axonal regeneration after ONC, together with improved retinal function assessed by PERG. Furthermore, the deletion of HDAC3 enhanced the phagocytic function of myeloid cells to effectively remove apoptotic cells and myelin debris, both in vivo and in vitro. These protective effects were associated with the deletion of HDAC3 specifically in macrophages, since microglial-only deletion of HDAC3 did not preserve RGC count or function. The enhanced efferocytosis function of HDAC3 KO macrophages was at least partly dependent on increasing the expression of the phagocytic tyrosine kinase receptor, MerTK. The deletion of myeloid HDAC3 enhances efferocytosis, leading to neuroprotection, regeneration, and functional recovery following ONC. Targeting myeloid-HDAC3 presents a novel therapeutic strategy for TON.

SARS-CoV-2 RNA contains guanine-rich sequences that form secondary structures known as G quadruplexes (G4s). The SARS-CoV-2 nonstructural protein (NSP13) resolves G4s due to its helicase and ATPase activity, a process essential for viral replication. Here, we tested the effects of synthetic G4s on SARS-CoV-2 replication. In agreement, a synthetic G4 DNA 20 mer, consisting exclusively of guanines linked by a phosphorothioate backbone (designated GQ20-PTO), inhibited the replication of various SARS-CoV-2 variants in human lung cell cultures. Mechanistically, GQ20-PTO bound to NSP13 and inhibited its helicase and ATPase activity. Independent of its antiviral effects, GQ20-PTO additionally suppressed IFNβ and IL-6 (but not TNFα) signaling and the formation of reactive oxygen species, processes known to contribute to hyperinflammation in severe COVID-19. Hence, G4 quadruplexes like GQ20-PTO represent a novel class of DNA-based compounds for COVID-19 treatment with the potential to interfere with both SARS-CoV-2 replication and the uncontrolled inflammation associated with life-threatening COVID-19.

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases and is one of the leading causes of cancer-related death worldwide. Although traditional therapies such as chemotherapy, radiotherapy and molecular targeted therapy, as well as immunotherapy, have made substantial progress, drug resistance and tumour recurrence remain significant challenges. Immunogenic cell death (ICD), a special type of cell death, has emerged as a cutting-edge strategy for NSCLC treatment due to its unique immune activation mechanism. ICD orchestrates immunogenic tumour cell death via coordinated endoplasmic reticulum stress and reactive oxygen species generation, resulting in the release of damage-associated molecular patterns (DAMPs). Through a synergistic mechanism, tumour-associated antigens are unveiled, antigen-presenting cells such as dendritic cells are activated, and T cell responses targeting tumour-specific antigens are triggered. These factors collectively act to reprogramme the immunosuppressive tumour microenvironment (TME). Preclinical trials have demonstrated that chemotherapy, radiotherapy and molecular targeted therapy enhance the antitumour effect by inducing ICD, providing new strategies for treating NSCLC. This review systematically summarises the induction strategies of ICD in the treatment of NSCLC and focuses on the progress in preclinical experiments and clinical trials. Additionally, the current paper discusses the core challenges and future development directions of ICD in NSCLC therapy, to provide novel insights into the optimised utilisation and clinical implementation of ICD induction strategies.

NF-κB signaling can be subdivided into canonical and noncanonical pathways, culminating in the transcriptional activity of RELA and RELB, respectively. However, the upstream signals that activate these transcription factors and their specific regulatory roles in pancreatic ductal adenocarcinoma (PDAC) remain incompletely understood. We investigated the differential activation and function of RELA and RELB in PDAC using transcriptome-wide gene expression profiling, genome-wide occupancy mapping, and epigenomic analysis. Temporal activation patterns were assessed following TNFα or TWEAK stimulation. Single-cell RNA sequencing and multiplex immunofluorescence staining were used to characterize activity in primary PDAC tissues. Motif enrichment and chromatin accessibility were evaluated to determine transcription factor binding dynamics and co-regulatory associations. We demonstrate that TNFα is the primary activator of canonical NF-κB signaling via RELA, while TWEAK selectively engages noncanonical signaling through RELB in PDAC. RELA and RELB display distinct temporal dynamics and regulatory activity. RELA binds to both open and closed chromatin and drives a broad transcriptional program, while RELB exclusively occupies pre-accessible chromatin regions co-enriched for AP1 motifs. Motif analysis reveals a particularly strong association of RELB with AP1 elements, suggesting selective co-regulation. Single-cell transcriptomic analysis and multiplex staining in primary tumors reveal distinct spatial and cellular distribution patterns, with RELA and RELB active in separate tumor and microenvironmental compartments. These findings underscore the distinct and complementary roles of TNFα and TWEAK in regulating NF-κB signaling in PDAC. TNFα engages a broader transcriptional program via RELA, whereas TWEAK targets a more selective set of genes marked by chromatin accessibility and AP1 co-binding through RELB. This study provides critical insight into the regulatory dynamics of NF-κB signaling in pancreatic cancer and highlights the specialized functions of RELA and RELB in modulating gene expression and tumor-microenvironment interactions.