Haematological and Neurological Expressed 1 (HN1) is an oncogene for various cancers and previously has been linked with centrosome clustering and cell cycle pathways. Moreover, HN1 has recently been reported to activate mTOR signalling, which is the regulator of ribosome biogenesis and maintenance. We explored the role of HN1 in mTOR signalling through various gain- and loss-of-function experiments using biochemical approaches in different cell lines. We demonstrated for the first time that HN1 is required for nucleolar organiser region (NOR) integrity and function. Immunoprecipitation-based association and colocalization studies demonstrated that HN1 is an important component of the mTOR-RPS6 axis, and its depletion results with reduced mRNA translation in mammalian cancer cell lines. This study also demonstrated that the depletion of HN1 leads to the irregular distribution of nucleolar structures, potentially leading to cell cycle deregulation as reported previously. Accordingly, components of the translation machinery aggregate with a distinct speckled pattern, lose their essential interactions and ultimately impair mRNA translation efficiency when the HN1 is depleted. These results suggest that HN1 is an essential component of the nucleolus, required for ribosome biogenesis as well as global mRNA translation.

Organoid technology, as a revolutionary biomedical tool, has shown immense potential in haematological research in recent years. By using three-dimensional (3D) cell culture systems constructed from pluripotent stem cells (PSCs) or adult stem cells (ASCs), organoids can highly mimic the characteristics of in vivo organs, thereby offering significant potential for investigating human organ development, disease processes and treatment strategies. This review introduces the development of organoids and focuses on their progress in haematological research, including haematopoietic-related organoids, immune-related organoids and organoids used for studying blood system diseases. It discusses the prospects, challenges and future outlook of organoids in the field of haematology. This review aims to provide the latest advancements and future directions of organoid technology in haematological research, offering references and insights into further exploration in this field.

Pathological changes in the locus coeruleus-norepinephrine (LC-NE) neurons, the major source of norepinephrine (NE, also known as noradrenaline) in the brain, are evident during the early stages of neurodegenerative diseases (ND). Research on both human and animal models have highlighted the therapeutic potential of targeting the LC-NE system to mitigate the progression of ND and alleviate associated psychiatric symptoms. However, the early and widespread degeneration of the LC-NE system presents a significant challenge for direct intervention in ND. Recent advances in regenerative cell therapy offer promising new strategies for ND treatment. The regeneration of LC-NE from pluripotent stem cells (PSCs) could significantly broaden the scope of LC-NE-based therapies for ND. In this review, we delve into the fundamental background and physiological functions of LC-NE. Additionally, we systematically examine the evidence and role of the LC-NE system in the neuropathology of ND and psychiatric diseases over recent years. Notably, we focus on the significance of PSCs-derived LC-NE and its potential impact on ND therapy. A deeper understanding and further investigation into the regeneration of LC-NE function could pave the way for practical and effective treatments for ND.

Pigs are important agricultural animals whose growth rate and meat production performance are related to muscle development. Musculoskeletal embryonic nuclear protein 1 (MUSTN1) participates in various biological processes, including myogenesis and growth in animals, but the physiological functions and mechanisms of porcine MUSTN1 on muscle development are unclear; thus, we aimed to elucidate them. We found that MUSTN1 was highly expressed in the muscles of fast-growing pigs. Functionally, MUSTN1 promoted myoblast proliferation and differentiation. MUSTN1 knockout mice exhibited reduced muscle mass and fibre cross-sectional area, decreased exercise endurance, and delayed muscle regeneration. Small muscle protein X-linked (SMPX) was identified as an interacting protein of MUSTN1, and its promotion of myogenic differentiation depended on MUSTN1. Furthermore, MUSTN1 stabilised SMPX and maintained myofiber morphology. This study suggests that MUSTN1 is a critical regulator in the control of muscle development and regeneration and is a potential target for animal genetic improvement and the treatment of human muscle disease.

TRAPPC2L is a core subunit of the Transport Protein Particle (TRAPP) complex, which is involved in vesicle transport and autophagy. Mutations in Trappc2l gene are associated with neurodevelopmental disorders, characterised by severe neurodevelopmental delays and varying degrees of muscle abnormalities. In this study, we found that the knockout of Trappc2l did not cause developmental abnormalities in both male and female mice. However, the male mice were completely infertile. Histological examination revealed that germ cell syncytial structures with multiple nuclear were formed in Trappc2l knockout mice from embryonic day 17.5 (E17.5) and the number and size of these structures gradually were increased at later developmental stages. The germ cells were completely lost at 2 weeks after birth. Further study found that germ cell syncytial structures were most likely formed by abnormal cell division but not cell fusion. We also found that meiosis-associated genes Stra8 and Sycp3 were expressed in Trappc2l-deficient germ cells during the embryonic stage. Our study demonstrated that Trappc2l is essential for germ cell development in male mice which is probably involved in keeping the mitotic quiescent state of male germ cells during the embryonic stage.

Herpesviruses rely on host RNA polymerae II (RNA Pol II) for their mRNA transcription, yet the mechanisms of which has been poorly defined, while certain herpesviruses can enhance viral gene transcription by altering the RNA Pol II location, modulating its phosphorylation, or directly interacting with RNA Pol II. However, the influence of herpesviruses on RNA Pol II transcription extends beyond these direct effects. Here, we present a novel mechanism by which the host cell cycle regulates viral gene transcription via RNA Pol II during infection by Anatid Herpesvirus 1 (AnHV-1), an avian alpha-herpesvirus. The results demonstrated that the formation of viral replication compartments (vRCs) and the subsequent recruitment of RNA pol II are positively correlated with AnHV-1 DNA synthesis. As viral DNA replication progresses, host cells are arrested in the S phase, which not only halts host gene transcription but also facilitates viral transcription. This cell cycle arrest in the S phase promotes viral DNA (vDNA) synthesis and vRC formation, which further enhances the preferential recruitment of RNA Pol II to viral promoters, enabling efficient viral gene transcription. We propose that this S phase arrest and the hijacking of RNA Pol II represent a novel mechanism by which AnHV-1 enhances viral transcription, offering a unique survival strategy compared to the known strategy in herpesviruses. These findings expand our understanding of herpesvirus–host interactions and highlight potential targets for antiviral strategies.

SARS-CoV-2 infection and the resultant COVID-19 pneumonia cause significant damage to the airway and lung epithelium. This damage manifests as mucus hypersecretion, pulmonary inflammation and fibrosis, which often lead to long-term complications collectively referred to as long COVID or post-acute sequelae of COVID-19 (PASC). The airway epithelium, as the first line of defence against respiratory pathogens, depends on airway basal stem cells (BSCs) for regeneration. Alterations in BSCs are associated with impaired epithelial repair and may contribute to the respiratory complications observed in PASC. Given the critical role of BSCs in maintaining epithelial integrity, understanding their alterations in COVID-19 is essential for developing effective therapeutic strategies. This study investigates the intrinsic properties of BSCs derived from COVID-19 patients and evaluates the modulatory effects of mesenchymal stem cells (MSCs). Through a combination of functional assessments and transcriptomic profiling, we identified key phenotypic and molecular deviations in COVID-19 patient-derived BSCs, including goblet cell hyperplasia, inflammation and fibrosis, which may underlie their contribution to PASC. Notably, MSC co-culture significantly mitigated these adverse effects, potentially through modulation of the interferon signalling pathway. This is the first study to isolate BSCs from COVID-19 patients in the Chinese population and establish a COVID-19 BSC-based xenograft model. Our findings reveal critical insights into the role of BSCs in epithelial repair and their inflammatory alterations in COVID-19 pathology, with potential relevance to PASC and virus-induced respiratory sequelae. Additionally, our study highlights MSC-based therapies as a promising strategy to address respiratory sequelae and persistent symptoms.

Vasculogenic mimicry (VM) represents a novel form of angiogenesis discovered in numerous malignant tumours in recent years. Unlike traditional angiogenesis, VM facilitates tumour blood supply independently of endothelial cells by enabling tumour cells to form functional vascular networks. This phenomenon, where tumour cells replace endothelial cells to form tubular structures, plays a pivotal role in tumour growth and metastasis. Tumour progression is influenced by a variety of factors, including immune components. The immune system serves as a critical defence mechanism by identifying and eliminating abnormal entities, such as tumour cells. This inevitably reminds us of the intricate connection between the immune system and VM. Indeed, in recent years, some studies have shown that immune responses and related immune cells play different regulatory roles in the formation of VM. Therefore, this review provides a comprehensive discussion on the mechanisms underlying VM formation, its interplay with the immune system, and the potential of leveraging immunotherapy to target VM.

Due to the lack of effective therapeutic approach, glioblastoma (GBM) remains one of the most malignant brain tumour. By in vitro investigations on primary GBM stem cells, we highlighted one of the underlying mechanisms of drug resistance to alkylating agents, the DNA damage responses. Here, flow cytometric analysis and viability and repopulation assays were used to assess the long-term cytotoxic effect induced by the administration of a fourth-generation platinum prodrug, the (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato) platinum(IV) named Pt(IV)Ac-POA, in comparison to the most widely used Cisplatin. The immunofluorescence studies revealed changing pathways involved in the DNA damage response mechanisms in response to the two chemotherapies, suggesting in particular the role of Poly (ADP-Ribose) polymerases in the onset of resistance to Cisplatin-induced cytotoxicity. Thus, this research provides a proof of concept for how the use of a prodrug which allows the co-administration of Cisplatin and an Histone DeACetylase inhibitors, could suppress DNA repair mechanisms, suggesting a novel effective approach in GBM treatment.

Glioblastoma multiforme (GBM) is the deadliest brain tumour with an extremely poor prognosis. Tryptophan catabolism could enhance an array of protumour-genic signals and promoted tumour progression in GBM. However, the mechanisms of oncogenic signalling under tryptophan catabolism and potential therapy targeting this pathway have not been completely understood. Interleukin 4-induced 1 (IL4I1) is newly defined as a tryptophan metabolic enzyme and the potential function in GBM cells still remains unclear. In our study, we found IL4I1 was upregulated in GBM patients and predicted poor prognosis. Upregulation of IL4I1 inhibited GBM ferroptosis in vitro and in vivo. Further, we found that indole-3-pyruvic acid (I3P) from tryptophan mediated by IL4I1 could scavenge free radical and had an impressive role in inhibiting ferroptosis. To clarify the potential mechanism of I3P in GBM ferroptosis, we performed transcriptomic analyses of GBM cells treated with I3P and found that Nrf2 related genes was upregulated. Further, we found that the ubiquitination of Nrf2 could be attenuate by I3P binding with Nrf2 directly. Knockdown of Nrf2 attenuated the induction of anti-ferroptosis by IL4I1, pointing to Nrf2 as a key mediator of this process. In vivo, overexpression of IL4I1 with ML385 in GBM xenografts promoted ferroptosis. Collectively, this study emphasises the crucial roles of IL4I1 in anti-ferroptosis through Nrf2 signalling pathway but not AHR pathway by catabolism tryptophan, suggesting IL4I1 and tryptophan reprogramming as potential therapeutic targets for GBM.

Keloids are complex pathological skin scars characterised by excessive growth of fibrous tissue and abnormal accumulation of extracellular matrix (ECM). Despite various treatment options available, the treatment of keloids remains a major clinical challenge due to high recurrence rates and inconsistent therapeutic outcomes. By collecting three keloid tissues and three normal skin samples and utilising single-cell RNA sequencing (scRNA-seq), we delved into the cellular heterogeneity and molecular mechanisms of keloids. Our study identified multiple fibroblast subpopulations within keloid tissue. Enrichment and cell–cell communication analyses revealed that POSTN-positive mesenchymal fibroblasts (POSTN+ mesenchymal fibs) are more prevalent in keloids and exhibit higher transforming growth factor β (TGF-β) signalling activity, potentially playing a central role in excessive fibrosis. In contrast, IGFBP2-positive fibroblasts (IGFBP2+ fibs) are more abundant in normal skin, insensitive to TGF-β and Periostin signalling, and possess anti-fibrotic potential, possibly related to limited tissue repair and regenerative capacity. Trajectory analysis inferred the differentiation states and patterns of different fibroblast subpopulations. Additionally, we explored the heterogeneity of endothelial cells, finding an endothelial cell subpopulation (EC10) exhibiting mesenchymal activation characteristics, which may work with specific fibroblasts to promote abnormal angiogenesis and endothelial-to-mesenchymal transition processes. Spatial transcriptomics analysis has shown that the proportion of IGFBP2+ fibroblasts relatively increases in acne keloidalis after hormonal treatment, further demonstrating their value as potential therapeutic targets. Ultimately, we separated these two subpopulations using flow cytometry, highlighting their opposing roles in the secretion of the ECM. These findings provide new insights into the pathogenesis of keloids and lay the theoretical foundation for the development of innovative anti-fibrotic treatment strategies.

Extrachromosomal circular DNA (eccDNA) has emerged as a critical area of cancer research due to its ubiquitous presence in tumour cells and significant role in tumorigenesis, progression and drug resistance. Recent studies demonstrate that eccDNA promotes cancer progression by influencing genomic instability, amplifying oncogenes, regulating gene expression and enhancing tumour cell adaptability to adverse conditions. While the precise mechanisms underlying eccDNA formation and its biological functions remain unclear, its potential applications in cancer diagnosis, prognosis and targeted therapy are gaining increasing recognition. This review summarises the latest advancements in eccDNA research, highlighting its potential as both a biomarker and a therapeutic target. Additionally, it emphasises the translational potential of eccDNA in clinical diagnostics and personalised treatment strategies, offering new perspectives for future cancer research and innovative therapies.