Cell Cycle最新文献

Human glycyl-tRNA synthetase (GARS), encoded by the GARS1 gene, is a key protein within the aminoacyl-tRNA synthetases family, responsible for catalyzing the attachment of glycine to its corresponding tRNA during protein synthesis. While aminoacyl-tRNA synthetases are primarily known for their role in translation, emerging evidence indicates that they also have non-canonical functions in physiological and pathological processes, including metabolism, angiogenesis, immune responses, and inflammation. This review integrates glycyl-tRNA synthetase evolutionary origins, isoform biology, structure function relationships, immune roles, and cellular stress evidence across bladder, prostate, breast, colorectal, and hepatocellular tumors. Unlike prior papers about GARS, we (i) distinguish cytosolic vs mitochondrial GARS isoforms and their detection pitfalls; (ii) synthesize non-canonical mechanisms (neddylation interfaces, extracellular vesicles-mediated C-ter and N-ter peptides, CDH6-dependent signaling); and (iii) provide a comparative reliability map across cancers, identifying urinary bladder cancer as the most substantiated indication with convergent transcriptomic, proteomic, metabolic, and preliminary translational evidence. Current literature is dominated by correlative and in-vitro studies, and prospective clinical validation is scarce. GARS is a promising but incompletely defined oncologic and immunobiologic node; targeted, standardized, and clinically anchored studies are now feasible and necessary.

Cytarabine (ara-C) and fludarabine (F-ara-A) are key drugs in leukaemia treatment. SAMHD1 is known to confer resistance to ara-C and F-ara-A, and we previously identified ribonucleotide reductase inhibitors as indirect SAMHD1 inhibitors in a phenotypic screen. The inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolic acid (MPA) was also a hit in this screen. IMPDH inhibitors (IMPDHi) have previously shown efficacy against KMT2A-rearranged (KMT2Ar) acute myeloid leukaemia (AML). We investigated whether IMPDH inhibition could enhance the effect of ara-C and F-ara-A in AML cell lines and primary AML samples, and whether this effect was linked to KMT2A status. We found that sensitivity to IMPDHi was independent of KMT2A status. IMPDHi synergized with ara-C and F-ara-A in a SAMHD1-dependent manner in a subset of AML cells, but not in acute lymphoblastic leukaemia cell lines. Mechanistically, IMPDHi depleted allosteric SAMHD1 activators GTP and dGTP, thereby increasing active triphosphate metabolites in SAMHD1-proficient, but not SAMHD1-deficient, cells. Our findings suggest that the addition of IMPDHi to ara-C and F-ara-A may have therapeutic benefits in some AML cases.

Cancer stem cells (CSCs) represent a highly specialized intratumoral compartment responsible for tumor initiation, metastatic dissemination, therapeutic resistance, and disease recurrence. A central conceptual challenge in CSC biology is their capacity to oscillate between a quiescent G₀ state and a proliferative, stem-like phenotype, reflecting a high degree of phenotypic plasticity. Although dysregulation of the G1/S checkpoint is a hallmark of malignant transformation, its mechanistic contribution to CSC identity and plastic behavior remains poorly defined.This review outlines a conceptual model that integrates aberrant G1/S control with CSC state transitions. We propose that defective checkpoint regulation accelerates CSC proliferation, leading to the progressive intracellular accumulation of Cyclin D, which in turn drives a self-reinforcing, rapid G1 progression through phosphorylation-dependent pathways that operate independently of the slower, transcription-driven Cyclin D-Rb-E2F regulatory axis. With continued cycling, depletion of key E2F-regulated DNA replication factors ensues, eventually forcing CSCs into a quiescent, biosynthetic restoration phase. During this interval, essential genomic replication and cell cycle machinery are replenished until microenvironmental or intracellular cues trigger reentry into the proliferative cycle, giving rise to another burst of accelerated division.Through these cyclical perturbations in the Cyclin D/E2F balance, CSCs undergo temporally governed shifts between quiescent and proliferative states, thereby sustaining plasticity, intratumoral heterogeneity, and treatment-resistant phenotypes. This model also identifies potential therapeutic strategies, such as leveraging stimuli-responsive delivery systems that exploit cyclic CSC vulnerabilities.

Migrasomes are membrane-bound vesicles that form on the retraction fibers at the trailing edge of migrating cells and are deposited along the migration path upon the rupture of these fibers. As inherently signal-rich complexes enriched with diverse bioactive components, migrasomes not only mediate intercellular communication and microenvironmental regulation but also provide novel mechanisms and potential targets for understanding physiological and pathological processes. Although research on migrasome functions is still in its infancy, accumulating evidence suggests that they not only expand existing biological knowledge systems but also exhibit unique potential in elucidating disease mechanisms, developing diagnostic biomarkers, and exploring therapeutic targets. This review summarizes the discovery, biogenesis, biological functions, and methodological advances in migrasome research, with a particular focus on their emerging roles in disease. Additionally, we discuss prevailing challenges and future directions, concluding with a perspective on the clinical translation of migrasomes in diagnostics and therapeutics.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant adverse effect of cancer therapies that profoundly disrupts the quality of life for patients. CIPN is characterized by sensory symptoms such as pain, tingling, and numbness, typically distributed in a "glove and stocking" pattern. Its underlying mechanisms remain incompletely understood, involving complex processes such as heightened neuronal excitability, alterations in ion channel function, neuroinflammation, and glial cell activation. MicroRNAs (miRNAs), small non-coding RNA molecules, play a pivotal role in regulating these processes by modulating gene expression and cellular functions. Emerging evidence suggests that specific miRNAs, including miR-30b-5p, miR-155, miR-124, and miR-21, are involved in regulating pathways that contribute to CIPN-related pain. These miRNAs influence the function of ion channels, glial cell activation, and neuroinflammation. MiRNAs hold significant promise as biomarkers for the early detection of CIPN. This review comprehensively examines the current understanding of miRNA-mediated mechanisms contributing to CIPN development. Key miRNAs implicated in modulating these pathways are discussed in detail, including their potential as diagnostic biomarkers and therapeutic targets. By integrating molecular insights with translational approaches, this review provides a framework for future research and clinical applications targeting miRNA pathways to mitigate CIPN and improve outcomes for cancer patients undergoing chemotherapy.

Autophagy and cellular senescence are fundamental determinants of tumor cell fate. p16^INK4a has emerged as a key regulator at the intersection of these processes, yet its mechanistic role in the autophagy - senescence axis remains incompletely defined. Understanding this interaction is essential for identifying novel therapeutic opportunities in oncology. A systematic literature search was conducted across PubMed, Web of Science, and Scopus for studies published between January 2000 and April 2025, yielding 10 eligible studies after the application of predefined criteria. Evidence shows a dual role of autophagy in tumor biology. In some models, autophagy increased p16^INK4a and senescence-associated β-gal activity, leading to stable growth arrest. Under stress conditions, however, it supported tumor cell survival despite senescence signals. Mechanistically, p16^INK4a acted both upstream, modulating autophagic flux, and downstream, as an effector of autophagy-induced senescence. Study heterogeneity limited direct comparisons. Autophagy and p16^INK4a interact bidirectionally to regulate senescence, representing a critical axis that can shift tumor cells between suppression and survival. Future research should prioritize standardized protocols, longitudinal models, and therapeutic evaluations to clarify whether targeting this pathway can be translated into effective cancer interventions.

Adipose tissue is central to energy homeostasis and endocrine function, and its dysregulation is a key driver of metabolic disorders. Exosomes, serving as critical intercellular messengers, mediate systemic metabolic responses by delivering bioactive cargo, including nucleic acids, proteins, and lipids. Mounting evidence identifies adipose-derived exosomes as potent mediators of obesity-related inflammation and glucose metabolic dysfunction, thereby contributing to insulin resistance and diabetic complications. This review summarizes the pivotal roles of exosomal microRNAs (miRNAs) and highlights their significant potential as a novel class of small RNA therapeutics. Unlike synthetic delivery systems, exosomal miRNAs constitute an inherent delivery vehicle that synergizes natural targeting efficiency with potent gene regulatory functions. This unique combination enables the precise coordination of complex gene networks involved in metabolic disease, offering a distinct advantage over conventional single-target approaches. Consequently, exosomal miRNAs are positioned as promising candidates for pioneering RNA-based therapies against pervasive conditions such as diabetes and cardiovascular disease.

Glioma has long been a threat to human health and new treatments are required to address this health problem. We here explored the potential use of benzbromarone as a supplement to existing chemotherapy strategies. The effects of benzbromarone on the proliferation and migration of C6 glioma cells were evaluated by MTT and wound healing assays. The effects of benzbromarone on cell cycle arrest and apoptosis in C6 glioma cells were determined by flow cytometry. The effect of benzbromarone on reactive oxygen species (ROS) production was determined through fluorescence microscopy and flow cytometry. Finally, the effect of benzbromarone on the NF-κB pathway was determined by western blotting and immunofluorescence. Benzbromarone inhibited the growth and migration of C6 glioma cells in a concentration-dependent manner. Benzbromarone also induced cell cycle arrest and apoptosis in C6 glioma cells, in addition to increasing ROS generation. Western blot analysis revealed that benzbromarone activated the NF-κB signaling pathway. Our results suggest that benzbromarone induces cytotoxicity through ROS production. These findings indicate the potential of benzbromarone as a treatment of glioma.

Insulin resistance (IR) is the main feature of type 2 diabetes mellitus. Furthermore, viral infection can aggravate the abnormal glucose metabolism in diabetic patients. GABBR1 can maintain normal glucose homeostasis, but its specific role in diabetes is not clear. We investigated the function of the GABBR1/miR-19b-3p/WNT2B axis in vitro and in vivo. miR-19b-3p and GABBR1 were overexpressed or knocked down in AML12 cells. Subsequently, these cells were treated with palmitic acid (PA) to induce damage or poly I : C to mimic viral infection. The degree of AML12 cell damage was assessed using the CCK-8 assay; inflammation levels were measured using ELISA; and IR indexes were determined using the Immunofluorescence kit and Western blot assay. The diabetic mice model was established to evaluate liver injury and IR. PA and poly I : C can reduce the activity of AML12 cells, increase apoptosis and inflammatory factor contents, weaken the ability of glucose uptake and consumption, enhance the production capacity, and reduce the level of GLUT4. GABBR1 mediates the targeted regulation of WNT2B by miR-19b-3p. PA and poly I : C also increased ALT, AST, inflammatory factors and miR-19b-3p levels, and decreased GABBR1 and WNT2B expression of mice. Liver cells showed swelling and many spherical lipid droplets. After miR-19b-3p knockdown and GABBR1 overexpression, the degree of liver injury and IR in AML12 cells and mice were alleviated. GABBR1 regulates miR-19b-3p/WNT2B axis to reduce liver injury, IR and inflammatory response, and improve the comorbidity of diabetes and viral infection. This pathway represents a potential therapeutic target for mitigating the comorbidity of diabetes and viral infection.

Mutations in ATP8B1 cause a spectrum of cholestatic liver disease, ranging from Progressive-Familial-Intrahepatic-Cholestasis type-1 (PFIC1) to Benign-Recurrent-Intrahepatic-Cholestasis type-1 (BRIC1). Manifestations of PFIC1 include severe pruritus, jaundice, and liver damage. Extrahepatic features sometimes observed in PFIC1 include sensorineural hearing loss, diarrhea, pancreatitis, and short stature. ATP8B1 was shown to translocate phospholipids across the plasma membrane; however, expression of ATP8B1 in many tissues and the range of pathological manifestations in ATP8B1 deficiency suggest diverse physiological functions of ATP8B1, and pleiotropic mechanisms regulating its activity. Recent studies suggest that phosphoinositides, including PIP2 and PIP3, can function as regulators, substrates, and binding partners of ATP8B1. New research shows that ATP8B1 modulates host immune system by regulating cleavage of pyroptotic-executioner Gasdermin D (GSDMD), and inflammation-resolution pathways such as phagocytosis/efferocytosis. Further mechanistic insights can accelerate development of new therapies for restoring membrane integrity, reducing inflammasome activity, and correcting metabolic imbalances caused by ATP8B1 dysfunction.