International Journal of Biological Sciences最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disorders and a growing public health concern. Sterile alpha motif and HD domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, is known for its roles in nucleotide metabolism, antiviral defense, and immune regulation, but its function in hepatocytes and contribution to MASLD pathogenesis remain unclear. In this study, we observed that hepatic SAMHD1 expression was markedly increased in MASLD patient samples and diet-induced MASLD mouse models. In vitro, mimicking MASLD-associated dyslipidemia with palmitic acid, oleic acid, and cholesterol upregulated SAMHD1 expression, an IFN-γ-induced protein, accompanied by increased IFN-γ receptor 1 expression and STAT1 activation in HepG2 cells. Functional studies using SAMHD1-overexpressing and knockdown hepatic cell lines, as well as hepatocyte-specific AAV-mediated SAMHD1 overexpression in vivo, demonstrated that SAMHD1 promoted lipid droplet accumulation. Conversely, hepatocyte-specific SAMHD1 knockout reduced steatosis and liver injury in diet-induced MASLD mouse models. Mechanistically, SAMHD1 enhanced the proteolytic activation of SREBP1 and SREBP2 by upregulating SCAP, S1P, and S2P in a cohesin complex-dependent manner. Collectively, these findings identify hepatocyte SAMHD1 as a promoter of liver steatosis through SREBP activation and highlight it as a potential therapeutic target for MASLD.

Prostate cancer (PCa), a most prevalent urologic malignancy in men, remains a therapeutic challenge due to limited targeted strategies. This study investigates heat shock protein 60 (HSP60) (HSPD1-encoded), employing multi-dimensional approaches to decipher its oncogenic role and develop siRNA-loaded extracellular vesicles (siRNA@EVs) for PCa targeted therapy. Bioinformatics screening identified HSPD1 overexpression in PCa, which was validated via qPCR/Western blot in clinical tissues and cell lines. Metabolomic-transcriptomic integration and molecular biology experiments revealed HSP60-mediated glycolytic reprogramming. EVs were harvested from UV-irradiated PCa cells via high-speed centrifugation. siRNA@EVs were constructed via electroporation and evaluated in vitro (glycolysis phenotyping: glucose consumption, lactate/pyruvate production, hexokinase activity, and ATP production) and in vivo using xenograft models. Data were analyzed using R 4.3.1 and GraphPad Prism 9.0 (two-tailed t-test, P < 0.05). Multiple bioinformatics analyses (DepMap/TCGA/HPA) confirmed that HSP60 is specifically overexpressed and associated with advanced PCa progression and poor prognosis. HSPD1 knockdown and pharmacological HSP60 inhibition suppressed proliferation, metastasis, and subcutaneous tumor growth, while overexpression exacerbated oncogenicity. Multi-omics integration revealed HSP60 enhances glycolysis via p53 suppression, driving metabolic reprogramming. siRNA@EVs achieved significant HSPD1 silencing, effectively inhibiting the proliferation and metastasis of PCa cells, and blocking xenografts tumor growth in nude mice with safety. siRNA@EVs targeting HSPD1 demonstrate precision therapeutic potential with robust efficacy and safety, offering a novel approach for targeted therapy in PCa.

In intensive duck production systems, vanadium (V) is widely used as a growth-promoting additive, but excessive supplementation poses health risks to ducks. Previous research indicated that V could cause damage to organs by disrupting the structure and function of mitochondria and the endoplasmic reticulum. However, the precise mechanism of mitochondrial-associated endoplasmic reticulum membranes (MAMs) in V-induced hepatotoxicity remains unclear. To fill this gap, this study employed network toxicology to analyze the hepatotoxicity of V, and further validated the pivotal roles of glucose homeostasis and ferroptosis in this process through targeted MAMs proteomics. The results indicated that V exposure increased liver dysfunction markers, disrupted hepatic cord structure, and widened ER-mitochondria gaps. Besides, V exposure up-regulated the levels of the IP3R-Grp75-VDAC1 complex in MAMs while promoting its dissociation. Moreover, the sequencing results of MAMs demonstrated that V primarily induced hepatotoxicity by disturbing the glycolysis/gluconeogenesis pathway. Notably, V exposure exacerbated lipid peroxides and Fe²⁺ accumulation while inhibiting the NADH/FSP1/CoQ₁₀ axis, down-regulating the expression levels of ferroptosis-related factors in livers. These findings demonstrated that dietary V overexposure impaired hepatic MAMs integrity, disrupted glucose homeostasis, and suppressed the NADH/FSP1/CoQ₁₀ axis, which ultimately induced ferroptosis-mediated liver injury in ducks.

Chronic stress is increasingly recognized as a critical factor influencing tumor progression, but its underlying mechanisms remain incompletely understood. This review examines the role of gut microbiota as a critical mediator linking chronic stress to tumor progression. Recent evidence suggests that chronic stress triggers gut dysbiosis, characterized by reduced microbial diversity, depletion of beneficial bacteria, and enrichment of potentially harmful species. We summarize the mechanisms by which chronic stress regulates gut microbial dysbiosis, including stress-related hormone signaling, intestinal inflammation, mucosal barrier disruption, and altered gut motility. Additionally, we examine how stress-induced dysbiosis contributes to tumor progression through immune suppression, metabolic reprogramming, enhanced tumor stemness, and potentially through barrier dysfunction, and chronic inflammation. We further discuss potential therapeutic interventions, including specific probiotics, prebiotics and other strategies that may help suppress tumor development by modulating the stress-microbiota-cancer axis. In conclusion, these emerging insights provide a foundation for novel therapeutic strategies that target the stress-microbiome-cancer axis, which may help suppress tumor progression and complement conventional cancer treatments to improve clinical outcomes in cancer patients.

Tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutant non-small cell lung cancer (NSCLC); however, acquired resistance remains a major clinical challenge. While lysosomes have been implicated in drug resistance, their precise role in EGFR-TKI resistance remains unclear. In this study, we found that EGFR-TKI, including gefitinib and osimertinib, impaired WWP2-mediated proteasomal degradation of LAPTM4B. Through analysis of clinical tumor samples, genetic manipulation, and functional assays, we identify the lysosomal protein LAPTM4B as a key driver of EGFR-TKI resistance by enhancing EGFR phosphorylation and downstream signaling. Mechanistically, LAPTM4B interacts with ATP1A1 and facilitates its endocytosis, while simultaneously preventing its degradation by suppressing TRIM8-mediated K63-linked ubiquitination and proteasomal turnover. This stabilization of ATP1A1 enhances lysosomal acidification, ultimately promoting EGFR-TKI resistance. To identify potential therapeutic strategies, we conducted an unbiased high-content drug screen and identified compounds that suppress LAPTM4B expression. These compounds synergistically enhance the efficacy of EGFR-TKIs in NSCLC models in vitro and in vivo, with minimal toxicity. Integrative analyses of patient tissue samples, cellular models, an animal model, and cancer databases highlight the critical role of the LAPTM4B-ATP1A1-lysosomal acidification axis in EGFR-TKI resistance, providing a promising therapeutic avenue for overcoming resistance in EGFR-mutant NSCLC.

Mitochondria-mediated apoptosis is the key determinant of glomerular podocyte injury. NOD-like receptor family pyrin domain proteins (NLRPs) are aberrant in clinical kidney diseases, but the role in podocyte mitochondrial dysfunction is unclear. Here, we first observed only NLRP6 expression change in nephrotic syndrome patients with proteinuria. Next, we found that mouse glomerular podocyte NLRP6 expression was increased in high fructose-induced proteinuria with mitochondria-mediated apoptosis. Importantly, Nlrp6 deficiency ameliorated these disturbances in mice. NLRP6 downregulation inhibited podocyte mitochondrial outer membrane permeabilization (MOMP)-associated apoptosis via suppressing B-cell lymphoma 2-related ovarian killer (BOK) under high fructose stimulation. However, high NLRP6 expression blocked the binding of Tripartite motif-containing protein 7 (TRIM7) with Bok mRNA 3' untranslated region, decreased mRNA decay, and thereby downregulated antioxidant protein family with sequence similarity 213, member A (FAM213A), resulting in mitochondria-mediated apoptosis in high fructose-exposed podocytes. A nephroprotective agent gastrodin was found to decrease NLRP6 and relieve mitochondria-mediated apoptosis caused by high fructose, possibly through promoting TRIM7-driven Bok mRNA degradation and FAM213A antioxidant effect. This study uncovered that high NLRP6 expression-driven mitochondria-mediated apoptosis could participate in podocyte injury and the suppression of NLRP6 by gastrodin may be an attractive therapeutic approach for podocyte injury.

Drug tolerant persister cells (DTPs) refer to a transient drug-tolerance sub-population of cancer cells characteristics of phenotype plasticity and heterogeneity. This adaptive cell state is a critical transitional phase, standing on the crossroad that cancer cells reacquire drug sensitivity or enter into the permanent drug resistance. Emerging evidences indicate the epitranscriptomic regulations, particularly RNA methylations are the important mechanism underline post-transcriptional regulations of genes expression across all RNA species. RNA is integral to gene expression as messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA), which play roles in transmitting information from DNA to the synthesis of functional proteins. Methylation modifications on these RNAs are prevalent and represent a well-recognized non-genetic mechanism, exerting multifaceted regulatory effects on nucleic acid metabolism, such as nucleotide precursor availability, RNA processing dynamics, sub-cellular localization, transcript stability and translational fidelity/ efficiency. This review systematically sorts out the relevant references, demonstrating recent advances on the knowledge of the patterns of methylation modifications on mRNA, tRNA and rRNA, and how these modifications drive the generation and development of DTPs, which hallmarks of epithelial-mesenchymal transition, metabolism shift and immune escape. And then clinical strategies are delineated, leveraging pharmacological modulators of RNA-modifying enzymes alongside non-pharmaceutical lifestyle advice, for the development of therapy strategies preventing DTPs-rooted tumor relapse in this anti-tumor armamentarium with cytotoxic reagents, targeted therapies and immunotherapies.

Colorectal cancer (CRC) poses a significant global health challenge, yet immune checkpoint blockade (ICB) therapy benefits only a small subset of patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumours. Through analyses of public single-cell and spatial transcriptomic datasets, primary mouse cell sorting and adoptive transfer experiments, flow cytometry, multiplex immunofluorescence, immunohistochemistry, and coimmunoprecipitation, we revealed that sentrin-specific protease 7 (SENP7) promotes regulatory B-cell (Breg) differentiation and inhibits senescence by activating the expression of the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) via deSUMOylation, thereby enhancing the expression of genes such as interleukin-10 (IL-10). Notably, targeting SENP7 in B cells improved the antitumour efficacy of anti-PD-1 therapy. These findings suggest that inhibiting SENP7 may offer a promising strategy to sensitize immunologically "cold" tumours to immune checkpoint blockade.

Drug resistance remains a major obstacle to successful chemotherapy, leading to treatment failure and tumor recurrence. Recent studies indicate that mutations in FAT Atypical Cadherin 1 (FAT1) contribute to drug resistance in cancer cells. However, the precise role and underlying mechanisms of FAT1 in breast cancer (BC) remain insufficiently explored. Here, we conducted a comprehensive genomic and transcriptomic analysis, identifying FAT1 as a crucial tumor suppressor gene in BC. Our study demonstrates that genomic alterations in FAT1 are associated with the Wnt/β-catenin pathway activation. We further show that FAT1 loss induces cyclophosphamide (CTX) resistance and leads to the upregulation of the Wnt signaling cascade, accompanied by the accumulation of CTNNB1 transcription factors. Notably, combination therapy effectively alleviates drug resistance by suppressing the Wnt pathway. These findings highlight the critical role of FAT1 loss in mediating CTX resistance in BC and provide insights into potential therapeutic strategies targeting the Wnt pathway.

Background: Radiotherapy (RT) remodels the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are key mediators of TME, yet how RT reprograms TAMs toward a programmed death ligand- 1(PD-L1)⁺ immunosuppressive phenotype remains unclear. Materials and Methods: Esophageal squamous cell carcinoma (ESCC) subcutaneous xenografts in immunodeficient mice received localized RT or sham treatment. Tumor-infiltrating PD-L1⁺ TAMs were quantified via multiplex immunofluorescence and flow cytometry. Extracellular vesicles (EVs) derived from irradiated ESCC cells (IR-EVs) were isolated and characterized by nanoparticle tracking analysis and transmission electron microscopy. Functional assays included co-culture of IR-EVs-educated macrophages with autologous CD8⁺ T cells. RNA sequencing identified DYNLL1-AS1 as the most upregulated lncRNA in IR-EVs. Mechanistic studies employed RNA pull-down, mass spectrometry, RNA immunoprecipitation, and dual-luciferase reporter assays. Clinical validation utilized ESCC specimens for RNA in situ hybridization. Prognostic significance was assessed via Kaplan-Meier and Cox regression analyses. Results: RT triggered ESCC cells to secrete DYNLL1-AS1-enriched EVs, which reprogrammed macrophages into PD-L1⁺ immunosuppressive TAMs. IR-EVs-educated macrophages suppressed CD8⁺ T cell proliferation and IFN-γ/ Granzyme B secretion. Mechanistically, DYNLL1-AS1 bound SEC22B, enabling its interaction with FOXP1 to activate PD-L1 transcription via promoter binding. In vivo, EVs carrying DYNLL1-AS1 counteract anti-PD-L1 therapy by suppressing CD8⁺ T cell function and promoting tumor growth. In ESCC patients, high DYNLL1-AS1 expression correlated with PD-L1⁺ TAM density, poor immunotherapy response, and reduced survival. Multivariate analysis confirmed DYNLL1-AS1 as an independent prognostic factor. Conclusions: Radiation-induced DYNLL1-AS1 in ESCC EVs drives PD-L1⁺ TAMs immunosuppression via SEC22B/ FOXP1 signaling. Combining DYNLL1-AS1 inhibition with PD-L1 blockade may reverse RT-induced immunosuppression, offering a transformative strategy for ESCC radio-immunotherapy.