Cell Death & Disease最新文献

Platelets are short-lived anucleate cells essential for primary hemostasis and recognized for their functions in thrombosis, immunity, antimicrobial defense, neurodegeneration, as well as cancer growth and metastasis. Their brief lifespan in circulation is controlled by the removal of sialic acid residues from the platelet surface (desialylation) and also the mitochondrial apoptosis pathway, with high expression of the anti-apoptotic protein BCL-X_L being required for platelet survival. This dependence on BCL-X_L has prevented the clinical deployment of recently developed small molecule inhibitors of BCL-X_L, which have promising activity in solid as well as liquid cancers but cause on-target thrombocytopenia. Here, we investigate the functional relationship between platelet desialylation and apoptosis to determine how cross-talk between these mechanisms may impact platelet lifespan. We find that platelets progressively lose sialic acid residues and become more primed for apoptosis while in circulation, resulting in aged platelets that are desialylated and highly prone to undergoing apoptosis. In addition, platelet desialylation via endogenous or exogenous factors directly increases their BCL-X_L dependence and accelerates apoptosis, which can be reversed by treatment with the sialidase inhibitor DANA (2,3-dehydro-2-deoxy-N-acetylneuraminic acid). Notably, young platelets recently released into circulation are less primed for apoptosis and less dependent on BCL-X_L for survival. Consistent with these changes in priming, platelets aged in vitro exhibit increasing expression of multiple pro-apoptotic proteins including BIM, BAK and PUMA along with increasing cleaved caspase 3. Leveraging the lower BCL-X_L dependence of young platelets, stimulation of de novo platelet production with the thrombopoietin receptor agonist romiplostim prevents BH3 mimetic-induced thrombocytopenia in vivo and may prevent severe platelet loss in patients treated with BCL-X_L inhibitors.

This study aimed to investigate the role of Piezo1 in the immune-inflammatory response during the pathogenesis of ankylosing spondylitis (AS) and its underlying mechanisms. RT-qPCR was used to evaluate the expression levels of Piezo1 and autophagy-related genes in the peripheral blood of AS patients. Correlation analyses were conducted to evaluate associations between Piezo1 expression and clinical characteristics of AS patients. Immunohistochemistry (IHC) and Western blotting were performed to determine the expression of Piezo1 and autophagy-related proteins in the synovium of AS patients. In vitro, the effects of Piezo1 and autophagy on primary monocyte-derived macrophages and fibroblast-like synoviocytes (FLS) from AS patients were investigated using Yoda1 and 3-MA interventions. Modulation of the immune-inflammatory response via the Piezo1-autophagy axis was examined through RT-qPCR, Western blotting, and ELISA. Finally, the role of Piezo1 in immune regulation was further assessed in proteoglycan-induced arthritis (PGIA) model using GsMTx4, a Piezo1 inhibitor. Piezo1 expression was markedly elevated in AS patients compared to healthy controls and showed a positive correlation with disease activity, duration, and autophagy levels. Mechanistically, increased Piezo1 expression induced M1 polarization of monocyte-macrophages, leading to increased autophagy and the upregulation of inflammatory factors. Additionally, Piezo1 enhanced autophagy and IL-6 activation in FLS. In the PGIA model, GsMTx4 inhibited autophagy hyperactivation, significantly reduced the immune-inflammatory response, and exerted a protective effect on spinal bone tissue. Immunofluorescence further confirmed that these effects might be associated with reduced autophagy and inflammatory cytokine expression in macrophages and FLS. These findings highlight the role of Piezo1 in AS pathogenesis, suggesting that Piezo1 may contribute to the immune-inflammatory response in AS through autophagy regulation.

As a pathological hallmark of Parkinson's disease (PD), a-synucleinopathy induces various cellular damages, including calcium overload, mitochondrial and autophagic dysfunction, ultimately resulting in dopaminergic neuron death. However, the hierarchy of these detrimental events remains unclear. It is well established that a-synuclein can induce calcium overload through diverse mechanisms. To assess whether calcium overload plays a crucial detrimental role, we established a calcium overload model in Drosophila and conducted genetic screening. Our findings indicate that calcium overload caused mitochondrial damage and lysosomal dysfunction, leading to cell death, and these cytotoxic processes were significantly mitigated by the loss of Tousled-like kinase (TLK). Notably, the loss of TLK also ameliorated defects induced by a-synuclein overexpression in Drosophila. This suggests that calcium overload is a critical event in a-synucleinopathy. In mammalian cells and mice, calcium overload activated TLK2 (the homologue of Drosophila TLK) by enhancing TLK2 phosphorylation, which increases TLK2 kinase activity. Increased TLK2 phosphorylation was detected in the brains of GluR1^Lc and a-synuclein overexpression mice, suggesting that TLK2 is activated under these pathological conditions. Furthermore, TLK2 knockout mice exhibited rescue of multi-aspect cytotoxicity induced by calcium overload and a-synuclein overexpression. Our research demonstrates that TLK2 activation by calcium overload appears to be a pivotal step in the progression of PD. This finding provides a potential link between calcium overload, the subsequent mitochondrial and lysosomal dysfunction observed in the disease.

N4-acetylcytidine (ac4C) is a recently identified mRNA modification, with N-acetyltransferase 10 (NAT10) being the sole known enzyme responsible for its catalysis. However, the biological functions and regulatory mechanisms of NAT10-mediated ac4C modification in glioblastoma (GBM) remain largely unclear. In this study, we aimed to elucidate the regulatory pathways and functional implications of NAT10 and ac4C modification in GBM. We found that NAT10 is significantly upregulated in GBM, and its elevated expression is associated with disease progression and poor patient prognosis. Functionally, NAT10 promotes glioblastoma cell proliferation and migration in vitro and accelerates tumor growth in vivo. Mechanistically, we identified BOC mRNA, a member of the immunoglobulin superfamily of cell adhesion molecules, as a direct target of NAT10-catalyzed ac4C modification. This modification enhances both the stability and translational efficiency of BOC mRNA, thereby contributing to GBM progression. Furthermore, we demonstrate that HIF1α, a key transcription factor in the hypoxic response, directly activates NAT10 transcription by binding to hypoxia response elements HRE1 and HRE2, leading to increased ac4C modification of BOC mRNA under hypoxic conditions. Notably, pharmacological inhibition of NAT10 effectively suppresses its enzymatic activity, particularly under hypoxia, underscoring its potential as a therapeutic target in GBM. In summary, our findings reveal a critical role for NAT10-mediated mRNA ac4C modification in GBM oncogenesis and highlight NAT10 as a promising target for therapeutic intervention.NAT10 was upregulated in GBM, and NAT10 facilitated GBM progression in vitro and in vivo. Mechanistically, NAT10 catalyzed ac4C modification of BOC mRNA and maintained its stability and promoted translation. Besides, HIF1α influenced NAT10 and its ac4C writer function through transcriptional activation.

Cancer has become a leading cause of mortality worldwide, with alarming increases in incidence and mortality rates. Emerging evidence suggests that tRNA modification enzymes play a crucial role in cancer development by modulating codon-specific translation. In this review, we focus on 18 tRNA modification enzymes and elucidate their mechanisms of action and roles in disease. We highlight the functions and mechanisms of seven tRNA regulators that mediate favorable tRNA translation in tumorigenesis and cancer progression, providing deeper insights into their clinical potential as cancer-related biomarkers and prognostic indicators. These findings emphasize the need for further investigation into the therapeutic potential of tRNA modification enzymes in cancer management and their potential application in personalized cancer therapy and diagnostics.

Ischemia-reperfusion injury (IRI) represents a major challenge in liver transplantation, driving acute dysfunction and contributing to long-term allograft rejection. This process triggers a robust inflammatory response, leading to hepatocyte damage, senescence, and impaired liver regeneration. While the underlying mechanisms remain incompletely understood, increasing evidence highlights macrophage-derived signaling as a pivotal driver of hepatocyte fate during IRI. Here, we identify iRhom2 as a key regulator of immune-mediated liver injury, orchestrating macrophage-driven inflammation and hepatocyte senescence. iRhom2 is known to modulate the secretion of multiple cytokines by macrophages, yet its specific contribution to IRI-driven hepatocyte senescence has not been fully elucidated. We reveal a significant upregulation of iRhom2 in IRI+ reperfused allografts, particularly in Kupffer cells and monocyte-derived macrophages. Functional characterization in iRhom2-deficient macrophages revealed reduced ER stress, preserved mitochondrial function, and attenuated apoptosis, indicating a protective role against IRI-induced cellular damage. Proteomic profiling further uncovers iRhom2-dependent secretion of inflammatory mediators, with HMGB1 emerging as a critical damage-associated molecular pattern (DAMP) molecule in this context. Notably, HMGB1 release occurs independently of TACE catalytic activity, suggesting an alternative unexplored regulatory mechanism. Furthermore, co-culture experiments confirm that macrophage-derived HMGB1 directly induces senescence of human induced pluripotent stem cell-derived hepatocytes (hiPSC-Heps) under in vitro IRI condition, driving the up-regulation of key senescence markers and disrupting cell cycle dynamics. Strikingly, HMGB1 neutralization enhances hepatocyte viability and mitigates senescence, underscoring its pathogenic role. Additionally, HMGB1 knockdown in macrophages protects hepatocytes, though p21 expression remains unaffected, hinting at additional senescence pathways. Our findings establish iRhom2 as a central orchestrator of macrophage-driven hepatocyte dysfunction in IRI and suggest that targeting the iRhom2-HMGB1 axis could represent a promising therapeutic strategy to improve post-transplant liver recovery and long-term graft survival.

Genomic instability is a hallmark of cancer, encompassing both sequence and structural alterations that drive tumor evolution and heterogeneity. The APOBEC3 family of deoxycytidine deaminases has emerged as a major source of mutagenic activity in cancers. R-loops are RNA-DNA hybrids and structural barriers that interfere with replication and transcription. Among the APOBEC3 family, APOBEC3C (A3C) is particularly worthy of attention for its upregulation, driving the DNA replication stress tolerance in response to replication stress-inducing drug gemcitabine. However, the molecular mechanisms of gemcitabine resistance and regulatory circuitries mediated by A3C remain largely unknown, especially in checkpoint-deficient tumors. Initially, we screened that A3C was a putative transcriptional target of p53, and p53-deficient H1299 cells harboring A3C elicited a chemoresistant phenotype upon gemcitabine treatment both in vitro and in vivo. A3C expression enhanced Chk1-dependent S-phase checkpoint activation, thus slowing down replication fork progression and facilitating DNA repair. Pull-down assay and proteomic analysis identified that A3C had a specific interaction with the RNA helicase DDX5, which coordinately played critical roles in R-loop resolution. In contrast to A3C, DDX5 expression attenuated Chk1-dependent S-phase checkpoint activation. Knockdown of DDX5 in A3C-proficient H1299 cells attenuated gemcitabine-induced Chk1 activation and enhanced the therapeutic index of gemcitabine by promoting R-loop accumulation. Therefore, we conclude that A3C/DDX5/R-loop complex may impair the sensitivity of gemcitabine by modulating Chk1 dynamics and DNA replication/damage response machinery.

Although the clinical observation of hematologic toxicity related to radiotherapy has been recognized for a long time, the underlying mechanisms remain to be fully explored. Here, we established a mouse model of reduced dietary intake (dietary restriction, DR, 30% reduction in food intake compared to age-matched and gender-matched mice) following X-ray radiation exposure to investigate the impact of reduced dietary intake on hematopoiesis after irradiation. We found that post-irradiation DR significantly and persistently suppressed hematopoiesis and notably impaired the regenerative capacity of hematopoietic cells. Compared to ad libitum (AL) fed mice, post-irradiation DR led to sustained upregulation of the DNA damage response (DDR) signaling pathway in hematopoietic cells, even 14 days to 1 month after irradiation, along with delayed DNA repair. Further investigation revealed that DR suppressed the post-irradiation activation of the pentose phosphate pathway (PPP). Inhibition of PPP by 6-Aminonicotinamide (6-AN) in AL mice mimicked the impairment of hematopoiesis observed in DR mice, while activation of PPP by AG1 in DR mice rescued the impairment of DNA repair and hematopoiesis in these mice. Additionally, we conducted a retrospective analysis of 101 cancer patients who received pelvic radiotherapy and found that patients with lower Body Mass Index (BMI) experienced more severe reductions in white blood cells (WBCs), neutrophils, and lymphocytes. This study suggests that DR following irradiation inhibits hematopoiesis by suppressing PPP, providing a new approach to addressing radiotherapy-related myelosuppression and potentially offering solutions for improving refractory hematopoietic disorders associated with radiotherapy.

Mesenchymal stem cell (MSC) differentiation is a cornerstone of regenerative medicine with a wide range of applications in tissue engineering and translational therapies. However, the molecular mechanisms underlying MSC differentiation remain incompletely understood, preventing the full leveraging of their therapeutic potential. Central to these complex molecular networks are dynamic protein-protein interactions, with scaffolding proteins serving as master coordinators. GAIP-interacting protein C-terminus 2 (GIPC2) functions as an adaptor protein involved in mediating such interactions and may influence MSC fate by regulating differentiation-related signaling pathways. In this study, we identified GIPC2 as a novel regulator of adipogenic differentiation in human umbilical cord-derived MSCs (UC-MSCs). Mechanistically, GIPC2 interacts directly with pyruvate kinase M2 (PKM2) via its PDZ domain, promoting PKM2 nuclear translocation. In the nucleus, PKM2 facilitates the activation of sterol regulatory element-binding protein 1 (SREBP1), a transcription factor essential for lipid biosynthesis and adipocyte maturation. Our findings show that GIPC2 drives MSC adipogenic differentiation by orchestrating the PKM2-SREBP1 signaling axis. This study reveals a previously unrecognized regulatory mechanism, highlighting the pivotal role of GIPC2 at the intersection of metabolic regulation and transcriptional control. These insights not only deepen our understanding of MSC differentiation but also open new avenues for enhancing MSC-based therapeutic strategies.

Cutaneous T-cell lymphoma (CTCL) is a progressive and heterogeneous malignancy characterized by deregulated metabolic reprogramming and cancer stemness, with limited therapeutic options. Therefore, elucidating the mechanisms driving metabolic reprogramming and poor clinical outcomes in CTCL is imperative. Forkhead box protein M1 (FOXM1), an oncogenic transcription factor, plays a pivotal role in cancer pathogenesis by orchestrating metabolic reprogramming and stemness signaling, thereby contributing to therapeutic resistance. In this study, we investigated the therapeutic potential of FOXM1 inhibition in human CTCL cells. Both genetic and pharmacological targeting of FOXM1 markedly suppressed CTCL cell growth and proliferation by inducing programmed cell death (apoptosis and autophagy) via reactive oxygen species (ROS) generation. Mechanistic analyses revealed that the activation of the MAPK, particularly JNK activation, is crucial for thiostrepton-induced programmed cell death. Metabolomics profiling further demonstrated that thiostrepton treatment triggers ROS- and JNK-dependent alteration in metabolic pathways central to cancer hallmarks, including amino acid and lipid metabolism. Notably, FOXM1 inhibition abrogated stemness-associated metabolic reprogramming genes (KLF-4, Bmi1) and Skp2, while upregulating the tumor suppressor p21 in a JNK-dependent manner. Moreover, thiostrepton treatment sensitized the CTCL cells to proteasome inhibitor bortezomib, promoting apoptosis and autophagy. Collectively, these findings demonstrate that FOXM1 targeting disrupts the metabolic status and stemness features of CTCL cells via JNK activation, thereby offering novel insights into potential therapeutic strategies for overcoming therapeutic challenges in CTCL.