MedComm最新文献

{"title":"Serotonin (5-Hydroxytryptamine): Metabolism, Signaling, Biological Functions, Diseases, and Emerging Therapeutic Opportunities","authors":"Yuxin Zhang,&nbsp;Nan Wang,&nbsp;Louqian Zhang,&nbsp;Yan Zhuang,&nbsp;Qilei Xin,&nbsp;Xiaosong Gu,&nbsp;Chunping Jiang,&nbsp;Junhua Wu","doi":"10.1002/mco2.70383","DOIUrl":"https://doi.org/10.1002/mco2.70383","url":null,"abstract":"<p>Serotonin (5-hydroxytryptamine; 5-HT) is an evolutionarily conserved monoamine neurotransmitter that plays critical roles in various physiological systems, functioning as a neurotransmitter, hormone, and paracrine signaling molecule. This review synthesizes current research on 5-HT metabolism (biosynthesis, transport, and degradation), 5-HT receptor-mediated signaling pathways (seven receptor families and 14 subtypes), and broad biological functions of 5-HT. We emphasize the roles of 5-HT in both health and disease, with a particular focus on its emerging significance in the tumor immune microenvironment. Studies have shown that dysregulated 5-HT signaling is associated with various pathological conditions, including functional gastrointestinal disorders, psychiatric diseases, metabolic disorders, and cancer progression. Notably, this review describes novel mechanisms by which 5-HT modulates tumor immunity, including its effects on macrophage polarization, dendritic cell function, T cell activity, and PD-L1 expression, and it explores the therapeutic potential of targeting 5-HT-associated pathways. Promising therapeutic strategies that target 5-HT include combining selective serotonin reuptake inhibitors with immune checkpoint inhibitors, inhibiting key metabolic enzymes (e.g., Tph1 and MAO-A), and developing receptor subtype-specific agents (e.g., 5-HT₇R antagonists). These findings position the 5-HT system as a pivotal target for next-generation precision therapeutics across multiple disease domains.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70383","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ischemic Penumbra Protection: Beyond Brains or Not","authors":"Cesario V. Borlongan,&nbsp;Kaya Xu","doi":"10.1002/mco2.70370","DOIUrl":"https://doi.org/10.1002/mco2.70370","url":null,"abstract":"&lt;p&gt;In a recent study published in MedComm, Chuanjie Wu et al. [&lt;span&gt;1&lt;/span&gt;] reported important roles of transmembrane protein 30A (Tmem30a) and annexin V after ischemic stroke, in which treatment with recombinant annexin V reduced apoptosis in the penumbra and improved neurologic outcomes in a Tmem30a-dependent way. This study highlighted both the importance of communication between the central nervous system (CNS) and body organs after ischemic stroke and the necessity of the existence of penumbra in the communication.&lt;/p&gt;&lt;p&gt;Brain diseases represent a considerable social and economic burden worldwide. Patients suffering from brain diseases, including but not limited to stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), are still increasing despite great research advancements and emerging novel therapies. Previously, the CNS was regarded as a separate compartment, which was isolated from the rest of the body. Exogenous pharmacological modalities were unable to cross the blood–brain barrier (BBB). However, accumulating evidence over the past few years indicates that the CNS bidirectionally interacts with other major organs [&lt;span&gt;2&lt;/span&gt;]. These axes that mediate communications between the brain and body organs play an important role in maintaining homeostasis after brain diseases (Figure 1A). These axes also hold great potential for the exploration of novel mechanisms and therapeutic targets for brain diseases. The mediators might serve as new targets of brain protection.&lt;/p&gt;&lt;p&gt;CNS–body organ communications have been gradually recognized and accepted in recent years due to sensitive proteomics and single-cell RNA sequencing technologies, as well as the development of new experimental disease model systems. Several key types of mediators, including a broad array of signaling cytokines, nucleic acids, lipids, microbiomes, and metabolites, serve as the bridge for crosstalks between the brain and body organs. Increasing evidence has shown that these mediators exert a beneficial effect in many brain diseases. For example, plasma collected from voluntarily running mice could reduce baseline neuroinflammatory gene expression when infused into sedentary mice [&lt;span&gt;3&lt;/span&gt;]. Additionally, the complement cascade inhibitor, clusterin, could bind to brain endothelial cells and reduce neuroinflammatory gene expression in a mouse model. More importantly, patients with cognitive impairment displayed a higher level of plasma clusterin after a 6-month exercise. But not all patients exhibited improvement in cognitive function. These findings support the idea that the CNS–body crosstalk might exist, but the cytoprotective effects were variable among patients. Thus, these beneficial effects might also be closely associated with the micro-environment in the brain.&lt;/p&gt;&lt;p&gt;In the past 20 years, clinical neuroimaging tools have been able to discriminate the penumbra tissue with reduced blood flow but preserved metabolism, whic","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70370","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI Algorithm for Lung Adenocarcinoma Pattern Quantification (PATQUANT): International Validation and Advanced Risk Stratification Superior to Conventional Grading","authors":"Yuan Wang,&nbsp;Kris Lami,&nbsp;Waleed Ahmad,&nbsp;Simon Schallenberg,&nbsp;Andrey Bychkov,&nbsp;Yuanzi Ye,&nbsp;Danny Jonigk,&nbsp;Xiaoya Zhu,&nbsp;Sofia Campelos,&nbsp;Anne Schultheis,&nbsp;Matthias Heldwein,&nbsp;Alexander Quaas,&nbsp;Ales Ryska,&nbsp;Andre L. Moreira,&nbsp;Junya Fukuoka,&nbsp;Reinhard Büttner,&nbsp;Yuri Tolkach","doi":"10.1002/mco2.70380","DOIUrl":"https://doi.org/10.1002/mco2.70380","url":null,"abstract":"<p>The morphological patterns of lung adenocarcinoma (LUAD) are recognized for their prognostic significance, with ongoing debate regarding the optimal grading strategy. This study aimed to develop a clinical-grade, fully quantitative, and automated tool for pattern classification/quantification (PATQUANT), to evaluate existing grading strategies, and determine the optimal grading system. PATQUANT was trained on a high-quality dataset, manually annotated by expert pathologists. Several independent test datasets and 13 expert pathologists were involved in validation. Five large, multinational cohorts of resectable LUAD (patient <i>n</i> = 1120) were analyzed concerning prognostic value. PATQUANT demonstrated excellent pattern segmentation/classification accuracy and outperformed 8 out of 13 pathologists. The prognostic study revealed a distinct prognostic profile for the complex glandular pattern. While all contemporary grading systems had prognostic value, the predominant pattern-based and simplified IASLC systems were superior. We propose and validate two new, fully explainable grading principles, providing fine-grained, statistically independent patient risk stratification. We developed a fully automated, robust AI tool for pattern analysis/quantification that surpasses the performance of experienced pathologists. Additionally, we demonstrate the excellent prognostic capabilities of two new grading approaches that outperform traditional grading methods. We make our extensive agreement dataset publicly available to advance the developments in the field.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70380","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunoglobulin A Nephropathy: Molecular Pathogenesis and Targeted Therapy","authors":"Xu-Jie Zhou","doi":"10.1002/mco2.70382","DOIUrl":"https://doi.org/10.1002/mco2.70382","url":null,"abstract":"<p>Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerulonephritis globally, is characterized by mesangial IgA deposition and heterogeneous clinical trajectories. Historically, management relied on renin–angiotensin system inhibition and empirical immunosuppression, yet high lifetime kidney failure risk persists despite optimized care. This review synthesizes advances in molecular pathogenesis, highlighting how the traditional multi-hit hypothesis—while foundational for targeted therapy development—fails to capture IgAN's recurrent, self-amplifying nature. We introduce the “spiral hypothesis” as a dynamic model of cyclical immune-injury cascades, better explaining disease chronicity and necessitating sustained maintenance therapy. Emerging targeted therapies—including B-cell targeted agents (e.g., APRIL/BAFF inhibitors), complement inhibitors (e.g., iptacopan), and mucosal immunomodulators (e.g., TRF-budesonide)—enable early intervention addressing both upstream immunological drivers and downstream fibrotic pathways. We critically evaluate treat-to-target frameworks, defining remission endpoints (proteinuria &lt;0.3 g/day, hematuria resolution, estimated glomerular filtration rate slope &lt;−1 mL/min/year) and emphasizing biomarker-guided personalization. The paradigm shift toward proactive management prioritizes individualized therapeutic sequencing of novel agents based on dynamic risk stratification. Future priorities include optimizing protocols for high-risk phenotypes and refining long-term safety monitoring to ensure sustainable efficacy.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70382","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry","authors":"Barbara Vona,&nbsp;Bernd Wollnik,&nbsp;Nicola Strenzke,&nbsp;Tina Pangršič,&nbsp;Tobias Moser","doi":"10.1002/mco2.70363","DOIUrl":"https://doi.org/10.1002/mco2.70363","url":null,"abstract":"<p><i>CABP2</i> modulates presynaptic Ca_V1.3 Ca²⁺ channel function in inner hair cells (IHCs) and is required for indefatigable synaptic sound encoding. Biallelic variants in <i>CABP2</i> are associated with non-syndromic hearing loss (DFNB93). Otoacoustic emissions have been observed in an Italian family with a homozygous <i>CABP2</i> variant, indicating preservation of outer hair cell-mediated cochlear amplification. Hence, DFNB93 belongs to the hearing disorders caused by impairment of IHC synapses, termed auditory synaptopathy. DFNB93 mouse models have recapitulated findings and demonstrated that lack of CaBP2 impairs synaptic sound encoding by enhanced steady-state inactivation of Ca_V1.3 Ca²⁺ channels. Furthermore, preclinical studies have demonstrated feasibility of gene therapy. As growing evidence from <i>OTOF</i> clinical trials confirms synaptopathies as promising therapeutic targets for hearing restoration, <i>CABP2</i> ranks highly among the candidate genes for virus-mediated gene therapy to restore hearing. This perspective summarizes the preclinical gene replacement studies for hereditary hearing loss and outlines the characteristics that make genetic targets ideal for therapy development. It reviews the current literature on human <i>CABP2</i> studies, pre-clinical therapy development, and introduces a patient registry that aims to support research involvement with the <i>CABP2</i> patient community. We conclude with a preview of the next steps toward <i>CABP2</i> gene therapy clinical trials.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70363","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Reprogramming: A Crucial Contributor to Anticancer Drug Resistance","authors":"Yunhan Zhu,&nbsp;Weijie Yan,&nbsp;Lingfeng Tong,&nbsp;Jie Yang,&nbsp;Shengfang Ge,&nbsp;Jiayan Fan,&nbsp;Renbing Jia,&nbsp;Xuyang Wen","doi":"10.1002/mco2.70358","DOIUrl":"https://doi.org/10.1002/mco2.70358","url":null,"abstract":"<p>Cancer metabolic reprogramming is a fundamental hallmark that enables tumor cells to sustain their malignant behaviors. Beyond its role in supporting growth, invasion, and migration, metabolic rewiring actively contributes to anticancer drug resistance. Cancer cells not only reshape their own metabolism but also engage in aberrant metabolic crosstalk with nonmalignant components within the tumor microenvironment (TME). These metabolic alterations create multiple barriers to the efficacy of drug therapies, including chemotherapy, targeted therapy, and immunotherapy. Despite growing evidence, an integrated understanding of how metabolic reprogramming contributes to the development of drug resistance and how it may be therapeutically targeted to overcome the resistance remains incomplete. This review summarizes recent progresses in tumor-intrinsic and TME-associated metabolic alterations that contribute to drug resistance by sustaining metabolic needs and modulating nonmetabolic processes and explores the upstream regulatory mechanisms driving these changes, focusing particularly on glucose, lipid, and amino acid metabolism. We also discuss the current advances in the integration of small molecule inhibitors targeting cancer metabolism to address drug resistance. By consolidating mechanistic insights and therapeutic opportunities, this review highlights metabolic reprogramming as a promising intervention point to overcome anticancer drug resistance.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the miR-96-5p/Cathepsin B Pathway to Alleviate Neuron-Derived Neuroinflammation in Alzheimer's Disease","authors":"Kai Zheng,&nbsp;He-Zhou Huang,&nbsp;Dan Liu,&nbsp;Nadezda Brazhe,&nbsp;Jiajie Chen,&nbsp;Ling-Qiang Zhu","doi":"10.1002/mco2.70368","DOIUrl":"https://doi.org/10.1002/mco2.70368","url":null,"abstract":"<p>Alzheimer's disease (AD) is one of the leading causes of dementia in the elderly, and no effective treatment is currently available. Cathepsin B (CTSB) is involved in key pathological processes of AD, but the underlying mechanisms and its relevance to AD diagnosis and treatment remain unclear. In the present study, we found that CTSB expression was abnormally elevated in the hippocampus of 3×Tg mice and was regulated by miR-96-5p. Abnormalities in the miR-96-5p/CTSB signaling pathway were detected in the serum of both mild cognitive impairment and AD patients, and the combination of serum miR-96-5p and CTSB demonstrated strong diagnostic efficacy for cognitive impairment (AUC = 0.7536). Abnormalities in the miR-96-5p/CTSB signaling pathway in AD may be associated with Aβ pathology, and neuronal CTSB can be released extracellularly to reactivate adjacent astrocytes. Ultimately, the reconstitution of the miR-96-5p/CTSB signaling pathway effectively rescued astrocyte reactivity and memory impairment in AD. Our findings suggest that the neuron-derived inflammatory mediator CTSB reactivates adjacent astrocytes and mediates memory impairment in early AD. The combination of serum miR-96-5p and CTSB represents potential serum biomarkers for cognitive impairment, and targeting the neuronal miR-96-5p/CTSB pathway may serve as a promising therapeutic strategy for AD.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic Islet Cell Hormones: Secretion, Function, and Diabetes Therapy","authors":"Jinfang Ma,&nbsp;Mao Li,&nbsp;Lingxiao Yang,&nbsp;Qingxing Xie,&nbsp;Rongping Fan,&nbsp;Xi Lu,&nbsp;Xing Huang,&nbsp;Nanwei Tong,&nbsp;Zhenyu Duan","doi":"10.1002/mco2.70359","DOIUrl":"https://doi.org/10.1002/mco2.70359","url":null,"abstract":"<p>The pancreatic islets of Langerhans, which are composed of α, β, δ, ε, and PP cells, orchestrate systemic glucose homeostasis through tightly regulated hormone secretion. Although the precise mechanisms involving β cells in the onset and progression of diabetes have been elucidated and insulin replacement therapy remains the primary treatment modality, the regulatory processes, functions, and specific roles of other pancreatic islet hormones in diabetes continue to be the subject of ongoing investigation. At present, a comprehensive review of the secretion and regulation of pancreatic islet cell hormones as well as the related mechanisms of diabetes is lacking. This review synthesizes current knowledge on the secretion mechanisms of insulin, glucagon, somatostatin, ghrelin, and pancreatic polypeptides, emphasizing their functional crosstalk in diabetes. Emerging advances include CRISPR-based β-cell regeneration, bioengineered islet transplantation, and bioelectronic interventions aimed at restoring pancreatic function. Future research directions highlight artificial intelligence-guided prediction of hormone dynamics, therapeutics targeting the gut microbiome–islet axis, and tissue-engineered artificial islets. By integrating mechanistic insights, physiological roles, and translational innovations, this review outlines precision strategies for targeting islet hormone networks, offering a roadmap toward restoring metabolic equilibrium in diabetes.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70359","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA Modifications in Health and Disease","authors":"Shiqi Li,&nbsp;Ping Luo,&nbsp;Junli Fan,&nbsp;Yirong Li,&nbsp;Jiancheng Tu,&nbsp;Xinghua Long","doi":"10.1002/mco2.70341","DOIUrl":"https://doi.org/10.1002/mco2.70341","url":null,"abstract":"<p>RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine, and pseudouridine, serve as pivotal regulators of gene expression with significant implications for human health and disease. These dynamic modifications influence RNA stability, splicing, translation, and interactions, thereby orchestrating critical biological processes such as embryonic development, immune response, and cellular homeostasis. Dysregulation of RNA modifications is closely associated with a variety of pathologies. This review systematically synthesizes recent advances in understanding how dynamic RNA modifications orchestrate health and disease. We critically review the m6A modifications, the most abundant RNA methylation, its association with diseases, and regulations by post translation. We evaluate three interconnected themes: disease mechanisms, where dysregulated m6A drives oncogenesis (e.g., METTL3-mediated hypermethylation in breast cancer) and contributes to neuropsychiatric/cardiovascular disorders; homeostatic functions, spanning embryogenesis (maternal-to-zygotic transition), tissue regeneration (YTHDF1 in muscle), and immune regulation; therapeutic frontiers, including enzyme-targeting strategies (FTO inhibitors, METTL3 stabilizers) and diagnostic approaches. Our analysis reveals that context-dependent RNA modification networks operate as biological “switches” whose dysregulation creates pathogenic cascades. We further propose a novel framework for targeting these networks using multiomics integration. This review establishes RNA modifications as central targets for precision medicine, while highlighting critical challenges in clinical translation that demand interdisciplinary collaboration.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dehydrocostus Lactone Effectively Alleviates Inflammatory Diseases by Covalently and Irreversibly Targeting NLRP3","authors":"Qi Lv,&nbsp;Yishu Zhang,&nbsp;Juan Wang,&nbsp;Weijiang Lin,&nbsp;Ying Xie,&nbsp;Hongqiong Yang,&nbsp;Xunkai Yin,&nbsp;Zhenzhen Zhu,&nbsp;Yifan Cui,&nbsp;Yang Hu,&nbsp;Li Zeng,&nbsp;Yinan Zhang,&nbsp;Xubing Chen,&nbsp;Jian Liu,&nbsp;Lihong Hu","doi":"10.1002/mco2.70367","DOIUrl":"https://doi.org/10.1002/mco2.70367","url":null,"abstract":"<p>The activation of nucleotide oligomerization domain-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of various inflammatory diseases. The natural product oridonin possesses a novel mechanism for NLRP3 inhibition and a unique binding mode with NLRP3, but its poor anti-inflammatory activity limits further application. After virtual screening of diverse natural product libraries, dehydrocostus lactone (DCL) was considered as a potential NLRP3 inhibitor. DCL effectively inhibited caspase-1 cleavage and release of IL-1β in mouse and human macrophages at an extremely low concentration of 10 nM, comparable to MCC950. Mechanistically, our study assigned DCL a novel role in disrupting NLRP3 inflammasome assembly and ASC oligomerization. Excluding the influence on potassium/chloride ion efflux, calcium ion influx, and production of mitochondrial ROS, DCL formed a covalent bond with cysteine 280 in NACHT domain of NLRP3, thereby inhibiting the interaction between NLRP3 and NEK7. Furthermore, DCL exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including dextran sulfate sodium-induced colitis, 2,4,6-trinitrobenzenesulfonic acid-induced Crohn's disease, LPS-induced septic shock, and monosodium urate-induced peritonitis. Our findings identify NLRP3 as the direct target of DCL, positioning DCL as a promising lead compound for treatment of NLRP3 inflammasome-related diseases.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70367","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}