Cell Death Discovery最新文献

Necroptosis is a highly inflammatory form of regulated cell death driven by Receptor-Interacting Protein Kinase 3 (RIPK3), which plays a crucial role in immune responses, inflammatory diseases, and tumor microenvironment modulation. Beyond driving cell death via MLKL phosphorylation, RIPK3 also activates NF-κB signaling, promoting cytokine production and immunogenic responses. However, the regulatory mechanisms governing RIPK3-dependent NF-κB activation remain largely unclear. Here, we identify Growth Arrest and DNA Damage-inducible β (GADD45β) as a novel regulator of RIPK3 activities. We show that GADD45β directly binds RIPK3 in a RHIM-independent manner, interfering with NEMO-RIPK1-RIPK3 complex formation and limiting RIPK3-mediated NF-κB activation. Furthermore, inducible expression of GADD45β selectively suppresses RIPK3-induced proinflammatory signaling without promoting caspase-dependent apoptosis and markedly reduces CXCL8 (IL-8) production during necroptotic stimulation. GADD45β also improves long-term cellular survival under sustained inflammatory stress. Our findings reveal GADD45β as a critical modulator of RIPK3-driven immune responses and suggest a potential therapeutic strategy for fine-tuning immunogenic cell death.

Chemoresistance in non-small-cell lung cancer (NSCLC) remains a significant clinical challenge, often exacerbated by the tumor microenvironment's hypoxic conditions. Hypoxia has been implicated in promoting autophagy and contributing to chemoresistance, yet the underlying mechanisms are not fully elucidated. In this study, we investigated the role of EIF2AK3 in hypoxia-induced autophagy and cisplatin (DDP) resistance in NSCLC cells. Our findings demonstrated that hypoxia upregulates EIF2AK3 expression, leading to enhanced autophagy, as indicated by increased LC3-II/I ratios. Pharmacological inhibition of autophagy with 3-MA effectively reversed hypoxia-induced DDP resistance. Mechanistically, hypoxia-activated EIF2AK3 enhanced autophagy and decreased DDP sensitivity in NSCLC cells via PI3K/AKT signaling, independent of mTOR activity. Activation of autophagy by rapamycin counteracted the effects of EIF2AK3 knockdown on both autophagy and PI3K/AKT signaling. Consistently, EIF2AK3 silencing in xenograft models enhanced the therapeutic efficacy of DDP by suppressing autophagy and attenuating PI3K/AKT activation. Collectively, our findings indicate that EIF2AK3 is a critical regulator of hypoxia-triggered autophagy in NSCLC, and targeting EIF2AK3-mediated PI3K/AKT signaling may represent a promising strategy to overcome cisplatin resistance.

Vascular calcification (VC) is a common pathological state that often accompanies calcium-phosphorus metabolism disorder and chronic kidney diseases (CKDs). Vascular smooth muscle cell (VSMC) has been widely acknowledged as one of the main cell types involved in this process. Niacin, a lipid-lowering reagent, has been demonstrated to be beneficial in atherosclerotic disease, but its role in vascular calcification remains unexplored. Restricted cubic spline (RCS) analysis of clinical datasets revealed an inverse correlation between dietary niacin intake and abdominal aortic calcification (AAC). Our data showed that niacin treatment remarkably reduced VSMC osteogenic differentiation. Moreover, niacin treatment alleviated CKD and vitamin D₃-induced vascular calcification in C57BL/6J mice. Mechanistically, we for the first time demonstrated that niacin inhibited vascular calcification via maintaining both Sirtuin 1 (SIRT1) and Sirtuin 6 (SIRT6) levels. Further, we verified that niacin increased SIRT1 and SIRT6-mediated autophagy flux in VSMC. Our findings reveal that niacin exerts anti-calcification effect via maintaining both SIRT1 and SIRT6, providing novel therapeutic strategies in the treatment of vascular calcification.

Endoplasmic reticulum (ER) stress is a central adaptive response that maintains proteostasis under diverse metabolic and environmental challenges. In cancer, ER stress and lipid metabolism form a tightly coupled, bidirectional regulatory network that integrates protein quality control with lipid remodeling. Through the unfolded protein response (UPR), ER stress reprograms lipid synthesis, oxidation, and storage to sustain energy balance and membrane integrity. Conversely, dysregulated lipid accumulation disrupts ER homeostasis and amplifies stress signaling, creating a feedback loop between metabolic and proteostatic imbalance. Proteostasis systems, including the ubiquitin-proteasome system (UPS) and autophagy, cooperate with UPR signaling to fine-tune this adaptive balance and enhance tumor survival under stress. This review highlights the bidirectional crosstalk between ER stress and lipid metabolism from the perspective of proteostasis-driven tumor adaptation and summarizes emerging therapeutic strategies such as small-molecule modulators, natural products, and combination therapies that target this adaptive network to overcome drug resistance and improve cancer treatment.

GlcNAcylation, a dynamic post-translational modification involving the addition of N-acetylglucosamine to serine and threonine residues, has emerged as a key regulatory factor in cellular metabolism and signaling. Ferroptosis, pyroptosis, and necroptosis are newly discovered forms of regulated cell death that play crucial roles in various physiological and pathological processes, including cancer development, neurodegeneration, and inflammation. This review aims to summarize the functions of O-GlcNAcylation in modulating these distinct cell death pathways, with a focus on their implications in disease mechanisms and potential therapeutic applications. We summarize the mechanisms by which O-GlcNAcylation modulates ferroptosis, pyroptosis, and necroptosis, and explore the potential of targeting O-GlcNAcylation as a promising therapeutic strategy for diseases characterized by dysregulated cell death.

Uveal melanoma (UM) is the most common intraocular tumor, and despite being rare, it accounts for nearly 13% of melanoma-related deaths. Indeed, patients with metastatic disease have typically survival rates of less than one year, with little improvement over the past few decades. Although TP53 mutations are uncommon in UM, recent findings highlight a dysfunctional p53 pathway in this cancer. Given its crucial role in mediating DNA damage responses, we analyzed the p53 protein functionality and downstream target activation in a panel of UM cell lines in response to standard-of-care treatments (i.e., cisplatin and proton-beam irradiation). Although most of the analyzed cells retained a wild-type p53, we observed a wide range of p53 protein stabilization and targets' activation. Recently, p53 isoforms have been recognized as modifiers of p53 activity, and their biology and functions depend on cellular context. We observed that UM cells express a broad spectrum of p53 isoforms, including Δ160p53α and Δ133p53β and the longer variants Δ40p53β and p53β. Interestingly, the down-regulation of the short p53 isoforms (Δ133/Δ160) revealed their contribution to promoting cell growth and in mitigating cell death triggered by standard-of-care therapies. Moreover, we verified the wild-type p53 status in a panel of 32 UM cases and analyzed the expression levels of p53 isoforms. Our results indicated a correlation between higher expression levels of Δ40p53α or Δ133p53γ isoforms and the development of more aggressive cancers. Our findings suggest that shorter p53 isoforms can promote cancer aggressiveness and therapy resistance, thereby providing crucial insights into UM pathogenesis.

Aminoacyl tRNA synthetases (AaRSs) are enzymes that play a role in maintaining translational fidelity by ensuring the accurate loading of amino acids to their cognate tRNAs. Mutations in the AaRSs are linked to diverse human diseases, including neurological disorders and various types of cancer. Among AaRSs, mutations in wars-1, a tryptophanyl tRNA synthetase, have been associated with cancer. Despite the extensive knowledge of WARS-1, there is no comprehensive understanding of its contribution to pathogenesis. In our previous study, we discovered the impact of WARS-1 on genomic integrity. We showed that WARS-1 depletion leads to a significant accumulation of free tryptophan (Trp), resulting in pronounced genomic instability, including the formation of chromatin bridges and micronuclei, and cell cycle arrest. In this study, we demonstrate that wars-1 knockdown induces apoptosis in the germline of C. elegans.

Bronchopulmonary dysplasia (BPD), a frequent complication in preterm infants receiving supplemental oxygen, is characterized by hyper-activation of macrophage inflammasomes, exuberant release of pro-inflammatory cytokines such as interleukin-1β (IL-1β), and Gasdermin D (GSDMD)-driven pyroptosis. However, the precise contribution of macrophage pyroptosis to BPD pathogenesis remains incompletely defined, and effective pharmacological interventions are still lacking. Using neonatal C57BL/6 wild-type (WT) and GSDMD-knockout (GSDMD^-/-) mice, we established a hyperoxia-induced BPD model (85% FiO₂, 14 days) and administered the GSDMD inhibitor disulfiram (50 mg kg⁻¹ intraperitoneally, once daily for 7 days). In vivo, we assessed lung histopathology, IL-1β levels, alveolarization, and vascular development; ex vivo, we isolated bone-marrow-derived macrophages (BMDMs) to quantify pyroptotic markers, M1/M2 polarization, and antibacterial capacity. GSDMD deletion or disulfiram treatment significantly attenuated macrophage and neutrophil infiltration, decreased pulmonary IL-1β concentrations, improved alveolar architecture and vascular density, and reduced overall cell death. BMDMs from GSDMD^-/- mice displayed diminished M1 polarization, enhanced bacterial killing, yet unaltered zymosan phagocytosis. Collectively, these findings identify GSDMD-mediated macrophage pyroptosis as a critical driver of BPD-related lung injury. Targeted GSDMD inhibition, whether genetic or pharmacologic, alleviates experimental BPD by down-regulating IL-1β and promoting alveolar development, thereby providing a promising therapeutic avenue for this devastating neonatal disorder.

Fibroblast-like synoviocytes (FLSs) contribute to the advancement of rheumatoid arthritis (RA) through enhanced metabolic reprogramming. This research focused on exploring the role and underlying mechanism of ubiquitin-specific protease 5 (USP5) in modulating the glycolysis and activation of RA-FLSs. Here, we identified that knockdown of USP5 in RA rats reduced synovial inflammation and glycolytic activity, as evidenced by decreased serum lactate levels and GLUT1 expression. In RA-FLSs, USP5 knockdown or treatment with 2-DG reduced cell proliferation, migration, invasion, cytokine production, and glycolysis, while increased apoptosis. Mechanistically, USP5 stabilized METTL14 by inhibiting its ubiquitination, while METTL14 enhanced the m⁶A modification of GLUT1 mRNA, thereby increasing its expression. Furthermore, overexpression of METTL14 partially reversed the effects of USP5 knockdown on glycolysis and inflammatory activation in RA-FLSs. Additionally, knockdown of METTL14 inhibited RA-FLS glycolysis and inflammatory activation by downregulating GLUT1. Collectively, USP5 stabilized METTL14-mediated m⁶A modification of GLUT1 by inhibiting the ubiquitination of METTL14, thereby enhancing glycolysis and inflammatory activation in RA-FLSs. These results suggest that the USP5/METTL14/GLUT1 axis could be a potential therapeutic target for RA.

Maf1 is a well-known RNA polymerase III repressor and functions as a tumor suppressor due to its role in inhibiting tRNA synthesis. However, the role of Maf1 in hepatocellular carcinoma (HCC) remains unclear. This study identified Aurora-A as a novel upstream regulator of Maf1 in HCC. We demonstrated that Aurora-A interacts with the C domain of Maf1 and phosphorylates it at Threonine-212, leading to increased protein stability and cytosolic accumulation of Maf1. Importantly, the Aurora-A-enhanced cytosolic localization of Maf1 promotes mitochondrial dysfunction and glycolytic activity, ultimately driving HCC cell proliferation. In contrast, mutation of the Thr-212 site abolishes these effects, confirming its critical role. Significantly, elevated Maf-1 expression correlates with unfavorable clinical outcomes in HCC, particularly among patients with high Aurora-A expression. Furthermore, HCC cells with overexpressed Maf1 have heightened sensitivity to Aurora-A inhibitors, suggesting a potential therapeutic vulnerability. Our study uncovers a non-canonical, oncogenic role of Maf1 in HCC and highlights the Aurora-A-Maf1 axis as a promising target for personalized cancer therapy.