Molecular biomedicine最新文献

Traditional antiviral strategies primarily rely on vaccines and virus protein-targeting drugs, which adopt a virus-targeting approach. However, the rapid mutation of viruses often leads to vaccine failure and drug resistance, highlighting the limitations of these conventional methods. Consequently, the development of novel broad-spectrum, host-targeting antiviral strategies has become a major research focus. Itaconate, an endogenous immunomodulatory metabolite, inhibits viral replication via post-translational modifications; however, its mechanism in suppressing viral endocytosis remains unclear. This study demonstrates that itaconate inhibits viral endocytosis by covalently modifying the Cys128 site of the adaptor-related protein complex 1 gamma 1 subunit (AP1G1), thereby providing a new target for host-directed antiviral drug development. It was found that itaconate binds to AP1G1 at Cys128, impairing its interaction with clathrin, which inhibits clathrin-mediated viral particle uptake and reduces cellular susceptibility to infection (i.e., the likelihood of cells being infected by viruses and undergoing infection). Furthermore, the natural product Licochalcone B was identified as targeting the same site as itaconate. In both BEAS-2B cell models and mouse infection models, Licochalcone B reduced pulmonary viral loads by over 95%. This study is the first to propose and validate the feasibility of inhibiting broad-spectrum viral infection by targeting AP1G1, elucidating a novel molecular mechanism of itaconate-mediated regulation, offering a new target for broad-spectrum antiviral drug development, and identifying Licochalcone B as a promising broad-spectrum antiviral agent.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive endocrine malignancies, characterized by rapid progression, extensive metastasis, and extremely poor prognosis. Despite advances in molecular oncology, the mechanisms driving ATC metastasis and therapeutic resistance remain largely unclear. Cancer cells that detach from the extracellular matrix must evade a specific form of apoptosis known as anoikis, and the ability to survive under these anchorage-independent conditions is a critical prerequisite for metastatic dissemination. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a master regulator of oxidative-stress responses and tumor adaptation, yet its function in governing anoikis resistance in ATC is not well understood. Here we demonstrate that Nrf2 expression is markedly upregulated in ATC tissues and cell lines, where its nuclear translocation drives transcriptional activation of anti-apoptotic and redox-protective genes including BCL-2 and SLC7A11. Under detachment stress, Nrf2 activation enhances cell viability, inhibits apoptosis, and facilitates multicellular aggregate formation, thereby promoting survival. Conversely, genetic silencing or pharmacological inhibition of Nrf2 with Brusatol markedly suppresses proliferation, invasion, and in vivo liver metastasis. Collectively, these findings identify Nrf2 as a pivotal driver of ATC anoikis resistance and metastatic competence through regulation of the BCL-2/SLC7A11 axis. Targeting the Nrf2-dependent survival pathway may thus offer a promising therapeutic strategy for this otherwise refractory malignancy.

Myocardial fibrosis is a serious complication in sepsis and leads to cardiac dysfunction. The carboxy terminus of Hsc70-interacting protein (CHIP), a U-box E3 ligase, defends against sepsis-caused cardiac injury. Here, we explored a novel therapeutic effect of α₁-adrenoceptor (α₁-AR) blockage on lipopolysaccharide (LPS)-induced myocardial fibrosis and clarified that its molecular mechanism was related to the restoration of CHIP expression. The results showed that LPS increased the release of norepinephrine (NE) in the myocardium and promoted myocardial fibrosis. NE promoted the cardiac fibroblasts (CFs) differentiation characterized by increased α-SMA and collagen I/III. Blockage of α₁-AR by prazosin apparently alleviated LPS-induced cardiac fibrosis and NE-caused CFs differentiation. Prazosin decreased phosphorylation of protein kinase C (PKC), p38 and Smad2/3, and reduced nuclear c-Jun level, as well as increased CHIP expression in the NE-stimulated CFs and the myocardium in LPS-treated mice. In vitro and in vivo data suggested that the overexpression of CHIP restrained α-SMA and collagen I/III production, and downregulated TGF-β receptor 1 (TGF-BR1) expression and Smad2/3 phosphorylation induced by NE or LPS respectively. Conversely, the knockdown of CHIP weakened the effect of prazosin. Furthermore, we innovatively revealed that α_1A-AR is the dominant α₁-AR subtype in CFs, and its specific antagonist, silodosin, eliminated NE-mediated CFs differentiation and LPS-induced myocardial fibrosis, which was consistent with the action of prazosin. These findings demonstrate the protective effect of α₁-AR blockage against LPS-mediated myocardial fibrosis, which is achieved by directly inhibiting the PKC-p38-Smad2/3 signaling pathway and promoting TGF-BR1 downregulation through restoring CHIP expression.

Accurate molecular subtyping is essential for guiding precision treatment and prognostic stratification in endometrial cancer (EC). However, current methods, based on Sanger sequencing and immunohistochemistry (IHC), are costly, time-intensive, and difficult to implement widely in routine clinical practice, particularly in resource-limited settings. To overcome these challenges, we developed a deep-learning pipeline that directly infers EC molecular subtypes from routine hematoxylin-and-eosin (H&E) whole-slide images (WSIs). The framework integrates super-resolution enhancement (SRResGAN), transformer-based lesion segmentation (MedSAM), and a ResNet-101 classifier for molecular subtype prediction, with an LSTM module for survival modeling. This retrospective study included 393 Chinese patients diagnosed between 2010 and 2018, all with ≥ 5 years of follow-up. Molecular subtypes-POLE^mut, mismatch repair-deficient (MMRd), p53abnormal (p53abn), and no specific molecular profile (NSMP)-were confirmed by Sanger sequencing and immunohistochemistry. The model achieved high classification accuracies (92% for POLE^mut and MMRd, 91% for p53abn, and 90% for NSMP), with a strong correlation between predicted and observed survival (R2 = 0.9692; MAE = 123 days). External validation on two independent cohorts (N = 35 and N = 83) confirmed robust generalizability across institutions. This study represents the first large-scale, multicenter, AI-based digital pathology model for EC molecular classification in China. The proposed workflow provides an automated, interpretable, and cost-efficient alternative to conventional molecular testing, supporting precision oncology, fertility-preserving management, and clinical decision-making in real-world practice.

Mutations in the signal transducer and activator of transcription 3 (STAT3) gene are strongly associated with Hyper-IgE Syndrome (HIES), a rare immunodeficiency disorder characterized by elevated levels of IgE and recurrent infections. The molecular mechanisms of how STAT3 dysfunction contributes to the pathophysiology of HIES are complex and not fully elucidated, especially in natural killer (NK) cells, which are crucial for the immune response against infections and malignancies. Employing single-cell sequencing and flow cytometry, we investigated the effects of STAT3 mutations on immune cell development, differentiation, and function. Our findings revealed an increased population of CX3CR1⁺CD57⁺ NK and NKT cells, suggesting their terminal differentiation and functional exhaustion. The trend of Th2 cell differentiation was identified in patients with STAT3 mutations and in STAT3 conditional knockout (CKO) mice. CUT&Tag analysis on CD4⁺ T cells from carriers of the STAT3 intron22 (2144 + 1G > A) mutation revealed enhanced binding of the variant STAT3 to the transcription start site of IL-4, which provides an explanation for the elevated peripheral IgE levels observed in these STAT3 mutation patients. This study enhances our understanding of how STAT3 mutations drive immunological dysregulation in HIES. The identified changes in immunological signature and transcriptional mechanisms offer new insights into therapeutic targets for HIES.

Gastrointestinal (GI) malignancies represent a significant global health burden, characterized by high mortality rates and profound resistance to conventional therapies. This necessitates the exploration of novel therapeutic vulnerabilities, and two recently discovered forms of regulated cell death, ferroptosis and cuproptosis, offer promising metabolism-centered strategies. Ferroptosis is a non-apoptotic pathway driven by iron-dependent lipid peroxidation, canonically suppressed by the glutathione peroxidase 4 (GPX4) axis. In contrast, cuproptosis is a distinct process wherein excess copper induces lethal proteotoxic stress through direct binding to lipoylated components of the tricarboxylic acid (TCA) cycle. Critically, these pathways are not mutually exclusive; instead, they are intricately connected through shared molecular nodes and metabolic dependencies, including redox homeostasis, key signaling proteins, and mitochondrial integrity. This review systematically examines the molecular crosstalk between ferroptosis and cuproptosis, highlighting the synergistic potential of their co-activation as a powerful anti-cancer strategy in GI tumors. We systematically evaluate both preclinical evidence and clinical studies for therapeutic interventions, ranging from small-molecule inducers to advanced nanoplatforms and immunotherapy combinations. Furthermore, we discuss the pressing challenges of identifying predictive biomarkers for patient stratification and overcoming adaptive resistance. Ultimately, deciphering the ferroptosis-cuproptosis nexus holds immense potential to unlock a new paradigm of synergistic therapies, paving the way for more effective clinical management of GI malignancies.

The pandemics of respiratory viruses pose a worldwide public health problem and bio-safety threat. Therefore, the development of high-throughput and accurate infection models is crucial for elucidating viral pathogenesis and accelerating countermeasures to address the evolving respiratory viruses and the unexpected outbreaks of emerging variants. Compared to traditional 2D cultures, organoids exhibit pronounced intercellular interactions, extracellular matrix signaling, and tissue-specific multicellular cooperation, thereby more accurately recapitulating the in vivo microphysiological environment. However, research involving animal models typically requires prolonged experimental timelines, making it challenging to perform high-throughput screening or rapidly develop therapeutic strategies within the valuable timeframe. Since the outbreak of SARS-CoV-2, organoids have significantly advanced basic virology research and demonstrated potential in replicating the pathological and immunological characteristics in human patients. This review provides a comprehensive summary of the theoretical foundations, methodological framework, and complete procedures for identification and validation in organoid construction, along with their applications in the investigation of various respiratory viruses, such as coronaviruses, the influenza virus, respiratory syncytial virus, and others. Overall, the development of organoids, in conjunction with the integration of interdisciplinary technologies, has significantly advanced our fundamental understanding of the immunopathology process of respiratory viral infections, improved research efficiency, and provided precise tools for translational medical research.

Cluster of differentiation 39 (CD39) and CD73 are ectonucleotidases that play pivotal roles in purinergic signaling. CD39 catalyzes the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and subsequently to adenosine monophosphate (AMP), while CD73 further catalyzes the hydrolysis of AMP to adenosine. These ectonucleotidases are expressed across diverse cell types and exhibit pleiotropic functions in immune regulation, physiological homeostasis, and disease pathogenesis. Recent preclinical studies have increasingly identified CD39 and CD73 as promising therapeutic targets in various disease states, particularly in cancer. This review provides a comprehensive summary of the current advancements in CD39 and CD73 research, emphasizing their structural characteristics, distribution, enzymatic and non-enzymatic activities, as well as their biological functions. We discuss the involvement of CD39 and CD73 in multiple disease states, including cancer, autoimmune disorders, inflammatory diseases, cardiovascular disorders, infectious diseases, and neurological disorders. Furthermore, we present existing preclinical and clinical research on reported CD39 and CD73 inhibitors, which include small-molecule inhibitors, antibodies, advanced delivery systems, and combinations with adenosine receptor antagonists, targeted therapy, immunotherapy, and chemotherapy, thereby providing a foundation for future investigations. The anti-tumor efficacy of these inhibitors, observed across various tumor types, is primarily mediated through adenosine-dependent mechanisms. Despite these encouraging preclinical findings, several challenges hinder the application of CD39 and CD73 inhibitors. It is essential to optimize and modify their structures, enhance dosage forms, and adjust both the dosage and timing of administration to achieve high selectivity while minimizing off-target effects. Future research is anticipated to concentrate on mechanistic exploration and rational drug design, while also broadening their therapeutic potential to encompass additional diseases.

Osteoporosis is a systemic skeletal disease. Genetic and environmental factors work together to cause increased bone resorption, decreased bone formation, bone remodeling imbalance, reduced bone mass, and increased bone fragility. The global incidence of osteoporosis is relatively high, and osteoporosis negatively affects health and quality of life. Prevention and treatment research has continuously attracted the attention of scholars worldwide, and there is an extremely urgent need to find effective and safe treatment plans. This review elaborates on the physiological structure of bones and the principal relationship between bones and osteoporosis. The molecular mechanisms of osteoporosis development, including genes, inflammation, oxidative stress, signaling pathways, intestinal microbiota, autophagy, and iron metabolism, are systematically reviewed. This review comprehensively summarizes the latest advancements in the diagnosis and therapeutic interventions for osteoporosis. The therapeutic interventions include Western medicine treatment, Chinese herbal medicine treatment, nonpharmacological management and emerging therapeutic strategies. This review explores in depth the advantages and disadvantages of Western medicine and Chinese herbal medicine treatments, highlights the challenges that Chinese herbal medicine treatment for osteoporosis must overcome, and reveals the gap between emerging treatment methods and clinical applications, as well as potential directions for osteoporosis research, aiming to provide valuable references for the treatment of osteoporosis in the future.

Cells constantly encounter environmental and physiological fluctuations that challenge homeostasis and threaten viability. In response to these cues, specific proteins and nucleic acids engage in multivalent interactions and undergo phase separation to form membraneless assemblies known as biomolecular condensates. Nuclear condensates include paraspeckles, nuclear speckles, and Cajal bodies, while cytoplasmic condensates include stress granules, processing bodies, RNA transport granules, U-bodies, and Balbiani bodies. These assemblies regulate transcription, splicing fidelity, RNA stability, translational reprogramming, and integration of signaling pathways, thereby serving as dynamic platforms for metabolic regulation and physiological adaptation. However, dysregulation of these condensates has been increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases, cancers, and viral infections, contributing to toxic protein aggregation, nucleic acid dysregulation, and aberrant cell survival signaling. This review provides a comprehensive synthesis of the molecular mechanisms governing condensation, delineates the diverse types and functions of major biomolecular condensates, and examines therapeutic approaches based on their pathophysiological relevance to disease development and progression. Furthermore, we highlight the cutting-edge technologies, including CRISPR/Cas-based imaging, optogenetic manipulation, and AI-driven phase separation prediction tools, which enable the real-time monitoring and precision targeting of cytoplasmic biomolecular condensates. These insights underscore the emerging potential of biomolecular condensates as both biomarkers and therapeutic targets, paving the way for precision medicine approaches in condensate-associated diseases.