Cell Death Discovery最新文献

beta1-adrenergic receptor (β₁-AR) belongs to G protein-coupled receptors, regulating cardiac physiological and pathological process through complex signaling pathways. Physiologically, the activation of β₁-AR produces positive chronotropic, positive inotropic and positive dromotropic effects in the heart. However, excessive or sustained activation of β₁-AR can cause myocardial injury, arrhythmias, and heart failure. The β₁-AR in the heart exhibits tissue-specific distribution patterns and subcellular localization features adapted to its function within cardiomyocytes. Upon ligand binding, the β₁-AR undergoes conformational changes and transmits signaling through G protein-dependent pathways (β₁-AR/Gs and β₁-AR/Gi) as well as a G protein-independent pathway (β₁-AR/β-arrestin) to regulate cardiac activity. Subsequently, the β₁-AR can either dissociate from G protein to undergo desensitization and terminate signal transduction, or it can be endocytosed into the cell, transported to the lysosome to be degraded, or returned to the plasma membrane to continue its function. Additionally, it has been found that β₁-AR can cause or exacerbate heart disease when abnormal changes occur in its distribution density, localization, and mediated downstream signaling pathways. Therefore, β₁-AR represents an important pharmacotherapeutic target for the treatment of cardiac diseases. Among the relevant therapeutic agents, β₁-AR blockers designed specifically against β₁-AR have evolved to the third generation. This review comprehensively analyzes β₁-AR from perspectives including its research history, expression, and distribution in the heart, protein structure, signaling pathways, and associations with cardiac diseases.

Chondrocyte senescence is a key driver of osteoarthritis (OA) progression. This study examined the role of the glycolytic enzyme PFKFB3 in regulating chondrocyte senescence during OA. Using a destabilization of the medial meniscus (DMM) mouse model, we found that PFKFB3 expression was reduced in human and mouse OA cartilage and in hydrogen peroxide-treated chondrocytes. PFKFB3 knockdown or overexpression in primary chondrocytes was achieved through RNA interference or lentiviral delivery, followed by RNA sequencing and molecular analyses. PFKFB3 loss impaired DNA damage repair, activated NF-κB signaling, elevated pro-inflammatory cytokines, and promoted chondrocyte senescence, whereas PFKFB3 overexpression enhanced DNA repair and alleviated OA severity. Pharmacologic inhibition of NF-κB reduced inflammatory and senescent phenotypes in PFKFB3-deficient chondrocytes. These findings indicate that PFKFB3 regulates chondrocyte senescence via NF-κB signaling and DNA damage responses, suggesting PFKFB3 as a potential therapeutic target for OA.

Prostate cancer (PCa) represents a leading cause of cancer-related morbidity in men worldwide, necessitating deeper insights into its molecular drivers. Circular RNAs (circRNAs) are increasingly recognized as key regulatory molecules in carcinogenesis; however, their functional significance in PCa pathogenesis and treatment resistance remains incompletely defined. Here, we identify circPPFIA2 as a novel clinically relevant oncogenic circRNA with dual roles in PCa progression and therapeutic resistance. CircPPFIA2 is markedly upregulated in PCa clinical specimens and cell lines. Through gain- and loss-of-function experiments in both cell-based and animal models, we established that circPPFIA2 drives oncogenic phenotypes by enhancing tumor cell proliferation, migratory capacity, and resistance to enzalutamide therapy. Mechanistic investigations revealed that circPPFIA2 functions as a competitive endogenous RNA (ceRNA), simultaneously sequestering tumor-suppressive miR-646 and miR-1200. This miRNA sponge activity facilitates post-transcriptional upregulation of ETS1, a critical effector of androgen receptor signaling and treatment resistance. This molecular interplay establishes the circPPFIA2/miR-646/miR-1200/ETS1 axis as a central driver of PCa progression and therapy resistance. To functionally validate this finding, we employed lipid nanoparticle (LNP)-mediated co-delivery of si-circPPFIA2 and enzalutamide, which effectively restored drug sensitivity and inhibited tumor growth in resistant PCa models. Our findings highlight circPPFIA2 as both a prognostic biomarker and a promising therapeutic target for advanced PCa, providing a rationale for developing circRNA-directed therapies to overcome treatment resistance.

The proliferation of early erythrocyte and the subsequent maturation are critical events during erythropoiesis, while how these two independent but interconnected processes are efficiently orchestrated during erythropoiesis is largely unknown. Prpf4 expression is enriched from Pre-Colony Forming Unit-Erythroid (PreCFU-E) to Nucleated Erythrocytes, especially in the CFU-E cells, implying that Prpf4 plays a critical role in erythropoiesis. Here, we demonstrate that prpf4 sequentially regulates erythrocyte proliferation and maturation during zebrafish definitive hematopoiesis. The data show that prpf4 mutation results in severe defects in erythropoiesis, characterized by a substantial reduction in erythroid cell numbers and impaired erythrocyte maturation. Further analysis indicates that prpf4 mutation leads to cell cycle arrest of erythrocytes at the S and G2/M phases, as well as a significant increase in erythrocyte apoptosis. Mechanistically, prpf4 mutation leads to DNA damage and the subsequent activation of the DNA damage response, triggering the ATM/CHK2-p53 signaling pathway. This process inhibits the proliferation of early erythrocyte and induces erythrocyte apoptosis. On the other hand, the data reveal that prpf4 mutation causes significant defects in skipped-exon during pre-mRNA splicing, accompanied by severe splicing defect in slc25a39 pre-mRNA. This results in a significant downregulation of slc25a39 mRNA, which partially impairs erythrocyte maturation during late erythropoiesis. In conclusion, we identify that prpf4 sequentially regulates early erythrocyte proliferation and subsequent erythrocyte maturation. This dual function of prpf4 partially explains how early erythrocyte proliferation and late maturation are efficiently coordinated during erythropoiesis.

Sepsis-induced acute lung injury (ALI) involves a complex interplay between immune cells and the pulmonary endothelium. However, the molecular regulators that coordinate this interaction remain poorly defined. In a murine sepsis model, we identified a subset of lung-resident macrophages characterized by robust IL-1β expression as pivotal contributors to lung damage. Single-cell RNA sequencing (scRNA-seq) delineated a distinct IL-1β⁺ macrophage population with pronounced pro-inflammatory transcriptional features and enhanced endothelial communication. These macrophages exhibited intensified ligand-receptor interactions with pulmonary endothelial cells, corresponding with elevated vascular leakage and histopathological evidence of injury. Immunoassays, Western blotting, and histopathology confirmed IL-1β upregulation during lung injury. Furthermore, metabolomics and in vitro co-culture experiments demonstrated that IL-1β impairs endothelial integrity and modulates metabolic activity. This study reveals a novel immune-metabolic axis whereby IL-1β⁺ macrophages orchestrate endothelial dysfunction and tissue injury in sepsis. Our findings highlight IL-1β as a potential therapeutic target for mitigating ALI in septic patients.

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.

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.

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.