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PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3–ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.Huang et al. show that, in response to chemotherapy, PTEN directly interacts with NLRP3 in myeloid cells to enhance inflammasome activation and antitumour immune responses.

NLRP3 inflammasome is involved in the pathology of multiple human inflammatory diseases but there are still no clinically available medications targeting the NLRP3 inflammasome. We have previously identified RRx-001 as a highly selective and potent NLRP3 inhibitor, however, it contains high-energy nitro functional groups and may cause potential processing problems and generates highly toxic oxidants. Here, we show that compound 149-01, an RRx-001 analogue without high-energy nitro functional groups, is a potent, specific and covalent NLRP3 inhibitor. Mechanistically, 149-01 binds directly to cysteine 409 of NLRP3 to block the NEK7-NLRP3 interaction, thereby preventing NLRP3 inflammasome complex assembly and activation. Furthermore, treatment with 149-01 effectively alleviate the severity of several inflammatory diseases in mice, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate crystals (MSU)-induced peritonitis and experimental autoimmune encephalomyelitis (EAE). Thus, our results indicate that 149-01 is a potential lead for developing therapeutic agent for NLRP3-related inflammatory diseases.

Excessive activation of the NOD-like receptor pyrin domain–containing protein 3 (NLRP3) inflammasome plays a key role in the pathogenesis of various inflammatory diseases. Despite the development of several NLRP3 inhibitors, no specific therapy has been approved for clinical use, underscoring the urgent need for safe and effective agents. Here, we demonstrate that ML345 acts as a highly potent and selective NLRP3 inhibitor with strong therapeutic potential for NLRP3-driven inflammation. ML345 effectively suppresses canonical, noncanonical, and alternative NLRP3 inflammasome activation pathways, without affecting other inflammasomes. Mechanistically, ML345 blocks NLRP3 inflammasome activation independently of its intrinsic insulin-degrading enzyme (IDE) inhibitory activity. ML345 binds to NLRP3 in a non-covalent manner and directly targets tyrosine 381 (Y381), disrupting its essential interaction with NIMA-related kinase 7 (NEK7), consequently preventing inflammasome complex formation. In vivo, ML345 is well tolerated and markedly alleviates inflammatory responses and pathology in mouse models of NLRP3-associated disorders, including systemic inflammation and miscarriage triggered by lipopolysaccharide (LPS). Compared with several previously reported NLRP3 inhibitors, ML345 exhibits superior selectivity and comparable or greater inhibitory potency. These findings establish ML345 as a safe and selective NLRP3 inhibitor with robust anti-inflammasome effects and highlight its potential as a promising therapeutic candidate for NLRP3-driven diseases.

The activation of NLRP3 inflammasome leads to cell pyroptosis and inflammatory cytokines secretion and gets involved in the development of many diseases, such as neuroinflammation and metabolic syndrome, but the drugs targeting NLRP3 are not clinically available for now. Through screening the small molecule library, we found that manoalide is a highly selective small molecule inhibitor of NLRP3. Mechanismly, manoalide inhibited the NLRP3 inflammasome activation by acting downstream of potassium efflux, chloride efflux and mitochondrial dysfunction. Moreover, manoalide blocked the interaction between NEK7 and NLRP3 by covalently binding to Lys 377 of the NLRP3 protein. Treatment of manoalide relieved the pathogenesis of experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our results identify manoalide as a selective and covalent NLRP3 inhibitor and suggest it has the potential for the treatment of NLRP3-associated diseases.

Local progression and metastasis remain the foremost impediments to long-term survival among patients with colorectal cancer (CRC). long non-coding RNAs (lncRNAs) have a pivotal role in the advancement of colorectal malignancies. The aim of the present study was to elucidate the functional role and underlying molecular mechanisms of the lncRNA AL445238.2 in CRC progression. In the present study, overexpression/knockdown lentiviral vectors, protein half-life assays and co-immunoprecipitation assays were used to explore the regulatory relationship among AL445238.2, ubiquitin-specific protease 4 (USP4) and BCL2, combined with Transwell assays, sphere formation assays and subcutaneous xenograft models to demonstrate their effects on colon cancer proliferation and stemness both in vitro and in vivo. The experimental findings revealed that AL445238.2 was highly expressed in CRC cells. AL445238 overexpression significantly enhanced the proliferation of DLD1 and SW480 cells, reduced extracellular lactate dehydrogenase release, diminished apoptotic activity and increased cellular stemness, as evidenced by increased CD133 expression and augmented tumor sphere formation, together with enhanced mitochondrial activity. RNA pulldown and immunofluorescence assays further demonstrated a direct interaction between AL445238.2 and USP4, with the two synergistically modulating the expression of the anti-apoptotic protein Bcl2 and the pro-apoptotic protein BAX to suppress apoptosis. Moreover, in in vivo assays, USP4 independently promoted cell proliferation, sustained stemness and enhanced mitochondrial function, thereby increasing tumor growth. Collectively, the findings of the present study revealed that AL445238.2, through its interaction with USP4, orchestrated the regulation of cell proliferation, apoptosis, stemness maintenance and migration in CRC cells, offering novel insights into the role of lncRNAs in cancer progression and highlighting potential therapeutic targets.

Background. miR-1251-5p was identified as a tumor suppressor in a variety of malignancies; however, its biological function in clear cell renal cell carcinoma (ccRCC) is unknown. Methods. The Cancer Genome Atlas (TCGA) database was used to download expression information, including miR-1251-5p, in 521 ccRCC tissues and 71 ordinary tissues, and bioinformatics was used to explore possible target mRNAs. The relationship between miR-1251-5p, target mRNA activity, and clinical factors was examined. To estimate the biological activity of miR-1251-5p and target mRNA in ccRCC cells, we used MTT, colony formation, enzyme-linked immunosorbent, and Transwell assays. We employed a dual-luciferase reporter assay and a western blot to examine the molecular mechanisms of miR-1251-5p in ccRCC cells. In addition, the expressions of miR-1251-5p and target mRNA were further verified in the GEO database. Results. Our findings revealed that miR-1251-5p binds with NPTX2’s 3′-UTR. In TCGA and GEO datasets, miR-1251-5p activity is found to be lower in ccRCC tissues than that in nearby conventional tissues, although NPTX2 activity is higher. In ccRCC sufferers, miR-1251-5p and NPTX2 act as biomarkers that indicate a bad prognosis. Meanwhile, in miR-1251-5p tissues, NPTX2 expression and multiple clinical variables (survival status, grade, T staging, N staging, M staging, and clinical stage) had significant differences p<0.05. Structurally, miR-1251-5p inhibited proliferation, migration, and immune escape of ccRCC cells by targeting NPTX2. Conclusion. Our findings indicate that miR-1251-5p constrained ccRCC cell advancement, migration, and immune evasion via targeting NPTX2, providing novel insights into ccRCC target treatment.

Background Epithelial-to-mesenchymal transition (EMT) and cancer stem-like cells (CSLCs) play crucial role in tumor metastasis and drug-resistance. Disheveled3 (DVL3) is involved in malignant behaviors of cancer. However, the role and potential mechanism of DVL3 remain elusive in EMT and CSLCs of colorectal cancer (CRC). Methods UALCAN and PrognoScan databases were employed to evaluate DVL3 expression in CRC tissues and its correlation with CRC prognosis, respectively. Transwell, sphere formation and CCK8 assay were used to assess metastasis, stemness and drug sensitivity of CRC cells, respectively. Western blotting and dual luciferase assay were performed to analyze the protein expression and Wnt/β-catenin activation, respectively. Lentiviral transfection was used to construct the stable cell lines. Animal studies were performed to analyze the effect of silencing DVL3 on tumorigenicity and metastasis of CRC cells in vivo. Results DVL3 was overexpressed in CRC tissues and several CRC cell lines. DVL3 expression was also higher in CRC tissues with lymph node metastasis than tumor tissues without metastasis, and correlated with poor prognosis of CRC patients. DVL3 positively regulated the abilities of migration, invasion and EMT-like molecular changes in CRC cells. Moreover, DVL3 promoted CSLCs properties and multidrug resistance. We further identified that Wnt/β-catenin was crucial for DVL3-mediated EMT, stemness and SOX2 expression, while silencing SOX2 inhibited DVL3-mediated EMT and stemness. Furthermore, c-Myc, a direct target gene of Wnt/β-catenin, was required for SOX2 expression and strengthened EMT and stemness via SOX2 in CRC cells. Finally, knockdown of DVL3 suppressed tumorigenicity and lung metastasis of CRC cells in nude mice. Conclusion DVL3 promoted EMT and CSLCs properties of CRC via Wnt/β-catenin/c-Myc/SOX2 axis, providing a new strategy for successful CRC treatment.

While understanding the drivers of river water quality is crucial, the dependence on ground observations hinders the accurate quantification of driver thresholds, as well as the scale-dependent effects of buffer zones. By transcending the limitations of ground observations, satellite remote sensing provides the spatially continuous data required to define effective buffer zones and determine the threshold intervals for natural and anthropogenic drivers, effectively promoting sustainable watershed management. Herein, we determined the total nitrogen (TN), total phosphorus (TP), permanganate index (CODMn), and turbidity in the Minjiang River of Fujian Province by synergizing Sentinel-2 imagery and in situ data (2021–2024). Subsequently, we further employed generalized additive models (GAMs) considering scale-dependent (50 m to 20 km) characteristics to screen and evaluate the natural–anthropogenic factors influencing the water quality indicators. The GAMs revealed that TN exhibited multiphasic responses to forest cover and water area, characterized by alternating positive and negative effects across their range. TP was found to be predominantly driven by agricultural and urban land use, showing clear scale–threshold effects. This study provides an integrated framework that moves beyond retrieval to quantitatively assess the impact of multi-scale natural–anthropogenic factors, offering actionable insights for precise watershed zoning and science-based management for the sustainable development of river systems.

The Yangtze Estuary is confronting unprecedented challenges due to intensifying human activities and a rising incidence of extreme weather events, which collectively threaten its essential functions in flood control, water supply, ecological sustainability, and navigation. In this study, the functions of the Yangtze Estuary under evolving hydrological and sediment conditions are comprehensively investigated and evaluated based on long-term measurement and statistical data. Using the comprehensive indicator evaluation method (CIEM) and the analytic hierarchy process (AHP), a River Functional Assessment Model for the Yangtze Estuary (RFAM-YE) is developed. The model incorporates four sub-models: flood control, water supply, ecological protection, and navigation demand. The southern branch of the Yangtze Estuary is selected as a case study for evaluation. The results show that in recent years, the flood control capacity, waterway stability, and ecological conditions in the southern branch have improved. However, the ongoing overall erosion trend poses a threat to water supply security and the integrity of biological habitats. The assessment results are generally consistent with actual engineering conditions, demonstrating the validity and applicability of the proposed model. Finally, recommendations for the protection and restoration of the Yangtze Estuary are proposed based on the evaluation. This study provides both theoretical and practical references for the management and conservation of the Yangtze Estuary.

Background Lymphovascular invasion (LOI), a key pathological feature of head and neck squamous cell carcinoma (HNSCC), is predictive of poor survival; however, the associated clinical characteristics and underlying molecular mechanisms remain largely unknown. Methods We performed weighted gene co-expression network analysis to construct gene co-expression networks and investigate the relationship between key modules and the LOI clinical phenotype. Functional enrichment and KEGG pathway analyses were performed with differentially expressed genes. A protein–protein interaction network was constructed using Cytoscape, and module analysis was performed using MCODE. Prognostic value, expression analysis, and survival analysis were conducted using hub genes; GEPIA and the Human Protein Atlas database were used to determine the mRNA and protein expression levels of hub genes, respectively. Multivariable Cox regression analysis was used to establish a prognostic risk formula and the areas under the receiver operating characteristic curve (AUCs) were used to evaluate prediction efficiency. Finally, potential small molecular agents that could target LOI were identified with DrugBank. Results Ten co-expression modules in two key modules (turquoise and pink) associated with LOI were identified. Functional enrichment and KEGG pathway analysis revealed that turquoise and pink modules played significant roles in HNSCC progression. Seven hub genes (CNFN, KIF18B, KIF23, PRC1, CCNA2, DEPDC1, and TTK) in the two modules were identified and validated by survival and expression analyses, and the following prognostic risk formula was established: [risk score = EXP DEPDC1 * 0.32636 + EXP CNFN * (− 0.07544)]. The low-risk group showed better overall survival than the high-risk group ( P  < 0.0001), and the AUCs for 1-, 3-, and 5-year overall survival were 0.582, 0.634, and 0.636, respectively. Eight small molecular agents, namely XL844, AT7519, AT9283, alvocidib, nelarabine, benzamidine, L-glutamine, and zinc, were identified as novel candidates for controlling LOI in HNSCC ( P  < 0.05). Conclusions The two-mRNA signature (CNFN and DEPDC1) could serve as an independent biomarker to predict LOI risk and provide new insights into the mechanisms underlying LOI in HNSCC. In addition, the small molecular agents appear promising for LOI treatment.