{"title":"Chronic Pain: Epidemiology, Pathophysiology, and Clinical Management.","authors":"Zhihao Shang, Zijiao Tian, Zhaoquan Wang, Zerui Yang, Ziyao Wang, Zikang Wang, Ziqing Wang, Xingyuan He, Yu Yan, Yuanfeng Gong, Siyuan Xu, Xinyi Li, Guihua Tian","doi":"10.1002/mco2.70756","DOIUrl":"https://doi.org/10.1002/mco2.70756","url":null,"abstract":"<p><p>Chronic pain represents a pervasive global health crisis and a leading cause of disability, yet its management remains challenged by the intricate heterogeneity of its underlying mechanisms. Transcending traditional symptom-based paradigms, chronic pain is now recognized as a distinct disease entity driven by multidimensional maladaptive plasticity. In this review, we synthesize the current landscape of chronic pain, bridging macrolevel epidemiological burdens with microlevel pathophysiological insights. We dissect the complex biological networks driving pain chronification, ranging from peripheral sensitization and ion channel dysfunction to central synaptic reorganization, spinal disinhibition, and maladaptive neuro-immune crosstalk involving glial activation and autoantibody-mediated mechanisms. Notably, we highlight emerging frontiers, including sexual dimorphism in immune signaling, metabolic reprogramming, and epigenetic memory. Furthermore, we critically evaluate the evolution of clinical management strategies, integrating pharmacological innovations, advanced neuromodulation, and digital therapeutics. Finally, we address the persistent translational chasm between basic discovery and clinical efficacy, advocating for a paradigm shift from \"one-size-fits-all\" approaches toward mechanism-based precision medicine-underpinned by robust biomarkers and deep phenotyping-to revolutionize therapeutic outcomes.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70756"},"PeriodicalIF":10.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13146384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848140","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":"Intratumoral Microorganisms in Tumors: Current Understanding and Emerging Therapeutic Strategies.","authors":"Haoling Zhang, Zengkan Du, Ping Lu, Aimin Jiang, Yadong Guo, Yawei Liu, Zhijing Song, Bing Dai, Wangzheqi Zhang","doi":"10.1002/mco2.70754","DOIUrl":"https://doi.org/10.1002/mco2.70754","url":null,"abstract":"<p><p>Recent advances in high-throughput sequencing, spatial omics, and integrative multiomics analyses have established reproducibly detectable microbial communities within tumor tissues, leading to the conceptualization of tumors as complex ecosystems encompassing an \"intratumoral microbiota.\" These microorganisms have increasingly been recognized as contributing to tumorigenesis, progression, and therapeutic response through interactions with the immune system, immunometabolic reprogramming of tissues, chronic inflammation, and genomic instability. Nevertheless, current evidence remains piecemeal and descriptive, with limited systematic consolidation of microbial composition, functional mechanisms, and translation to clinical application, particularly across tumor types and microenvironmental contexts. This review summarizes microbial diversity, tumor-type-specific associations, and multilayered mechanisms including immune modulation, metabolic reprogramming, and signaling rewiring, and discusses emerging applications such as biomarker discovery, prognostic stratification, and microbiome-targeted therapeutics. Special focus is placed on tumor microenvironment, microbiota-derived metabolites, and determinants of immunotherapy responsiveness. Overall, this review underscores the intratumoral microbiota as a dynamic and context-dependent regulatory layer in cancer biology and offers an integrated framework to realize microbiome-informed precision oncology, along with avenues for enhanced patient stratification and personalized therapeutic approaches.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70754"},"PeriodicalIF":10.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848121","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}
MedCommPub Date : 2026-05-03eCollection Date: 2026-05-01DOI: 10.1002/mco2.70752
Ce Cao, Bo Ma, Jian Zhang, Lili Yang, Zixin Liu, Haoran Li, Jianshu Song, Keer Zhang, Lei Li, Jianhua Fu, Jianxun Liu
{"title":"A Novel Mechanism of Salvianolic Acid B in Postmyocardial Infarction Cardiac Protection: PHB1-Driven Raf-ERK Pathway Activation Promotes Cardiomyocyte Mitosis.","authors":"Ce Cao, Bo Ma, Jian Zhang, Lili Yang, Zixin Liu, Haoran Li, Jianshu Song, Keer Zhang, Lei Li, Jianhua Fu, Jianxun Liu","doi":"10.1002/mco2.70752","DOIUrl":"https://doi.org/10.1002/mco2.70752","url":null,"abstract":"<p><p>Heart failure (HF) following myocardial infarction remains a leading cause of global morbidity and mortality, necessitating novel therapeutic strategies. Salvianolic acid B (SalB), one of the major active components of <i>Salvia miltiorrhiza</i> Bunge, has been shown to effectively reverse ischemia-induced myocardial infarction and improve cardiac function. Here, we report a novel mechanism by which SalB treats postmyocardial infarction heart failure by promoting cardiomyocyte re-entry into the cell cycle. A novel protein target of SalB, Prohibitin 1 (PHB1), was identified using chemical biology techniques. Experiments involving overexpression and knockdown of PHB1 have demonstrated that SalB promotes cardiomyocyte mitosis by acting on PHB1, which in turn upregulates the phosphorylation level of the Raf-ERK pathway. Molecular dynamics simulations provide a comprehensive explanation for the mechanism by which SalB enhances Raf phosphorylation. The findings reveal that SalB binds to the C-terminal of PHB1/2 heterodimer, inducing a conformational change that enhances Raf-ERK pathway activation via Akt-mediated phosphorylation, thereby promoting cardiomyocyte mitosis. The findings of this study propose a promising new molecular mechanism through which SalB can contribute to the preservation and restoration of cardiac function.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70752"},"PeriodicalIF":10.7,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848103","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}
MedCommPub Date : 2026-05-03eCollection Date: 2026-05-01DOI: 10.1002/mco2.70746
Xujie Zhang, Lin Sun, Laura Walsham, Yuexi Ma, Dang Ding, Mei Wang, Fabao Zhao, Jian Zhang, Zhao Wang, Shujing Xu, Xiangyi Jiang, Yang Zhou, Erik De Clercq, Christophe Pannecouque, Chin-Ho Chen, David C Goldstone, Xinyong Liu, Alexej Dick, Peng Zhan
{"title":"Discovery of 4-Quinazolinone-Containing Phenylalanine Derivatives as Potent, Resistant-Tolerant HIV Capsid Inhibitors.","authors":"Xujie Zhang, Lin Sun, Laura Walsham, Yuexi Ma, Dang Ding, Mei Wang, Fabao Zhao, Jian Zhang, Zhao Wang, Shujing Xu, Xiangyi Jiang, Yang Zhou, Erik De Clercq, Christophe Pannecouque, Chin-Ho Chen, David C Goldstone, Xinyong Liu, Alexej Dick, Peng Zhan","doi":"10.1002/mco2.70746","DOIUrl":"https://doi.org/10.1002/mco2.70746","url":null,"abstract":"<p><p>The HIV-1 capsid (CA) is a validated antiviral target that plays critical roles in both the early and late stages of the viral life cycle. Using structure-based strategy, we designed and synthesized a series of phenylalanine derivatives containing a 4-quinazolinone scaffold as novel HIV-1 CA inhibitors. Among them, <b>IC-2i</b> exhibited potent antiviral activity in MT-4 cells against HIV-1 NL4-3 (EC<sub>50</sub> = 0.65 ± 0.27 nM) and effectively protected cells from HIV-1 IIIB infection. SPR revealed that <b>IC-2i</b> interacts strongly with CA hexamers (<i>K</i> <sub>D</sub> = 2.7 ± 0.5 nM) with an extended residence time and competes with host factors CPSF6 and NUP153, disrupting CA assembly and disassembly. <b>IC-2i</b> retained activity against lenacapavir (LEN)-resistant strains, such as N74D (11-fold shift vs. 20-fold for LEN). Crystallographic analysis revealed that <b>IC-2i</b> binds at the CA NTD-CTD interface and forms hydrogen bonds with Thr107 and Ser41 (NTD-NTD interface). Pharmacological evaluation demonstrated favorable properties, including good plasma stability, low toxicity (SI > 1571), and suitable pharmacokinetics with a prolonged half-life following subcutaneous administration (<i>T</i> <sub>1/2</sub> = 19.9 h). Overall, this study identifies 4-quinazolinone-based phenylalanine derivatives as promising HIV-1 CA inhibitors and highlights <b>IC-2i</b> as a potential long-acting therapeutic candidate for HIV-1 treatment.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70746"},"PeriodicalIF":10.7,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848087","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}
MedCommPub Date : 2026-05-03eCollection Date: 2026-05-01DOI: 10.1002/mco2.70750
Jiaorong Qu, Wenqing Qin, Minghang Dong, Zhi Ma, Si Li, Runping Liu, Ranyun Chen, Changmeng Li, Xiaojiaoyang Li
{"title":"Liver Fibrosis: Molecular Pathogenesis and Therapeutic Interventions.","authors":"Jiaorong Qu, Wenqing Qin, Minghang Dong, Zhi Ma, Si Li, Runping Liu, Ranyun Chen, Changmeng Li, Xiaojiaoyang Li","doi":"10.1002/mco2.70750","DOIUrl":"https://doi.org/10.1002/mco2.70750","url":null,"abstract":"<p><p>Liver fibrosis is a common pathological process, leading to the development of end-stage liver diseases. It is triggered by various etiological drivers including viral hepatitis, metabolic-associated steatotic liver disease (MASLD), and cholestasis. Given the substantial impact of liver fibrosis on individuals and its associated mortality rates, effective management of this condition is crucial for improving public health. Despite a growing number of preclinical studies and clinical trials, a systematic synthesis remains lacking. In this review, the molecular panorama of liver fibrogenesis is summarized at first, encompassing etiological drivers of chronic liver injury, key cellular players, core signaling pathways, and extracellular matrix dynamics. Therapeutic interventions in preclinical or clinical stages are systematically classified into two main categories: etiological treatment as the foundational approach and mechanism-based antifibrotic therapies. Emerging and future therapeutic strategies, including those targeting gut-liver axis, gut microbiota, and cell-based therapies, are also addressed along with inherent challenges. Furthermore, future perspectives centered on precision medicine, combination therapies, novel target discovery, and advanced drug delivery systems are emphasized. This review offers a comprehensive overview of the etiologies, diagnostic approaches, pathogenic mechanisms, current development of antifibrotic agents, and prospects for future therapeutic directions of liver fibrosis.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70750"},"PeriodicalIF":10.7,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848106","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}
MedCommPub Date : 2026-04-26eCollection Date: 2026-05-01DOI: 10.1002/mco2.70748
Zheng Jiang, Mailudan Ainiwaer, Pengwei Zhao, Yansheng Hu, Xin Yang, Yu Xiong, Bin Zeng, Longhao Wang, Jun Liu, Fei Chen
{"title":"Laryngeal Transplantation in Cancer Patients: Evaluation of Surgical Outcomes and Functional Recovery.","authors":"Zheng Jiang, Mailudan Ainiwaer, Pengwei Zhao, Yansheng Hu, Xin Yang, Yu Xiong, Bin Zeng, Longhao Wang, Jun Liu, Fei Chen","doi":"10.1002/mco2.70748","DOIUrl":"https://doi.org/10.1002/mco2.70748","url":null,"abstract":"<p><p>Laryngeal transplantation offers a promising avenue for functional restoration following total laryngectomy, yet concerns regarding cancer recurrence and perioperative challenges persist. This pilot study evaluates the preliminary outcomes of a refined surgical technique and postoperative follow-up protocol specifically for cancer patients. Between 2023 and 2024, four patients underwent laryngeal transplantation at West China Hospital, with immunosuppressive therapy, microbial prophylaxis, and postoperative rehabilitation. Over a follow-up period ranging from 10 to 26 months, outcomes were heterogeneous. Two recipients (T4 laryngeal squamous cell carcinoma) achieved excellent functional recovery in swallowing and phonation with sustained rejection-free survival for 20 and 23 months and disease-free survival for 20 and 26 months, respectively, though both remained tracheostoma dependent. One of these survivors is currently undergoing treatment for graft rejection after unilateral cessation of immunosuppressants. The remaining two patients succumbed to severe pneumonia with sepsis and tumor recurrence at 10 and 11 months posttransplant. Functional assessments in surviving cases indicated progressive nerve regeneration, with optimal voice and swallowing outcomes achieved approximately 6-8 months postsurgery. Ultimately, these findings demonstrate the technical feasibility of laryngeal transplantation in a pilot cohort of cancer patients, providing critical data for future protocol refinement.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70748"},"PeriodicalIF":10.7,"publicationDate":"2026-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13111920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793546","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}
MedCommPub Date : 2026-04-26eCollection Date: 2026-05-01DOI: 10.1002/mco2.70747
Xiaocui Lu, Hui Fang, Yuan Liu, Chang Liu, Xuexiu Fang, Atsuko Matsunaga, Stephanie F Mori, Ting Zhang, Gavin Wang, George I Zhou, Miao Yu, Haocheng Ding, Jorge Cortes, Bo Cheng, Tianxiang Hu
{"title":"BCR-ABL1 Drives Transcriptional Reprogramming of Chronic Myeloid Leukemia Cells for Immune Evasion Through C/EBPβ.","authors":"Xiaocui Lu, Hui Fang, Yuan Liu, Chang Liu, Xuexiu Fang, Atsuko Matsunaga, Stephanie F Mori, Ting Zhang, Gavin Wang, George I Zhou, Miao Yu, Haocheng Ding, Jorge Cortes, Bo Cheng, Tianxiang Hu","doi":"10.1002/mco2.70747","DOIUrl":"https://doi.org/10.1002/mco2.70747","url":null,"abstract":"<p><p>Emerging immunotherapy holds promise to achieve treatment-free remission (TFR) for chronic myeloid leukemia (CML) patients, the development of which depends on full understanding of mechanisms driving immune evasion. Our current investigation in a mouse CML model revealed dominant presence of neutrophils during CML progression, accompanied by significant reductions and exhaustion of T cells. In coculture, these BCR-ABL1 expressing neutrophil-like CML cells significantly inhibited T cell proliferation. Gene expression profiling revealed that there was a global activation of both neutrophil markers and related immune suppression genes in these CML cells. Correlative analysis revealed strong correlations between the expression of BCR-ABL1 and immune suppression genes, suggesting a potential regulation of those genes by BCR-ABL1. Importantly, we identified CEBPB as a critical transcription factor that directly regulated the expression of master immune modulators TGFB1 and ARG2 through promoter binding, in both human and mouse CML samples. Therefore, blocking BCR-ABL1, or its downstream C/EBPβ, TGF-β and arginase with inhibitors or shRNAs rescued T cell suppression by neutrophil-like CML cells. Accordingly, combination treatment with targeted therapy using ponatinib and immunotherapy with anti-PD1 antibody not only provides rapid remission, but also delayed relapses after treatment discontinuation, justifying combination treatment for TFR of CML.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70747"},"PeriodicalIF":10.7,"publicationDate":"2026-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13111919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793490","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}
MedCommPub Date : 2026-04-25eCollection Date: 2026-05-01DOI: 10.1002/mco2.70738
Rongcheng Zhang, Yao Liang, Jingjing Li, Qianqi Chen, Ya Ding, Xizhi Wen, Baiwei Zhao, Wei Zheng, Junwan Wu, Qiong Zhang, Ziluan Chen, Qiuyue Ding, Linbin Chen, Renai Li, Ke Li, Qiming Zhou, Xiaoshi Zhang, Dandan Li
{"title":"Optimal Adjuvant Therapy Selection for Chinese BRAF V600-Mutant Stage III Melanoma: A Multicenter Efficacy Comparison of Targeted Agents, Immunotherapy, and Combinatorial Strategies.","authors":"Rongcheng Zhang, Yao Liang, Jingjing Li, Qianqi Chen, Ya Ding, Xizhi Wen, Baiwei Zhao, Wei Zheng, Junwan Wu, Qiong Zhang, Ziluan Chen, Qiuyue Ding, Linbin Chen, Renai Li, Ke Li, Qiming Zhou, Xiaoshi Zhang, Dandan Li","doi":"10.1002/mco2.70738","DOIUrl":"https://doi.org/10.1002/mco2.70738","url":null,"abstract":"<p><p>While adjuvant immunotherapy and BRAF/MEK inhibitors improve the outcomes for BRAF V600-mutant stage III melanoma, comparisons of long-term survival and safety of these therapeutic modalities are currently lacking in Chinese patients. We retrospectively analyzed data from patients with resected stage III BRAF V600-mutant melanoma who received adjuvant therapy between June 2013 and December 2023 across three centers in China. Note that 122 patients were included and categorized into interferon (<i>n</i> = 25), aPD-1 (<i>n</i> = 18), D/T (<i>n</i> = 62), and BRAFi/aPD-1 (<i>n</i> = 17) cohorts. The D/T group demonstrated a significantly longer median RFS compared to the interferon and aPD-1group (22.7 vs. 11.9 months, <i>p</i> = 0.005; vs. 12.5 months, <i>p</i> < 0.001). Similar results were obtained by restricted-mean-survival-time model. Patients who continued D/T beyond 1 year exhibited significantly improved RFS and DMFS compared to those who discontinued at 1 year duration (NR vs. 22.0 months, <i>p</i> = 0.048; NR vs. 22.5 months, <i>p</i> = 0.026). NOTCH4 and IL7R mutations may serve as prognostic and predictive biomarkers for long-term survival and targeted-immunotherapy efficacy, respectively. Adjuvant therapy with D/T may represent the most effective treatment strategy for Chinese patients with stage III melanoma harboring BRAF V600 mutations. A combination of BRAF-targeted therapy and aPD-1 immunotherapy provided comparable efficacy and may be an alternative for a specific patient.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70738"},"PeriodicalIF":10.7,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793541","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}
MedCommPub Date : 2026-04-25eCollection Date: 2026-05-01DOI: 10.1002/mco2.70745
Rongli Fang, Wei Wang, Li Zhang, Jiwei Huang, Lei Huang, Huibo Wu, Yuyin Qi, Lili Li, Liren Tan, Min Zhang, Jianheng Zhu, Xiang Peng, Kanghua Zhong, Ming Zou, Xi Yang, Qiuhua Wang, Changjun Nie, Chaorui Tang, Ning Tang, Lanlan Geng, Hanhan Chen, James E Vince, Hirokazu Kanegane, Xiaodong Zhao, Huifang Xian, Wenhao Zhou, Min Zhi, Yuxia Zhang, Zhanghua Chen
{"title":"XIAP Deficiency Impairs Colonic Tuft Cell Development and Predisposes to Crohn's Disease.","authors":"Rongli Fang, Wei Wang, Li Zhang, Jiwei Huang, Lei Huang, Huibo Wu, Yuyin Qi, Lili Li, Liren Tan, Min Zhang, Jianheng Zhu, Xiang Peng, Kanghua Zhong, Ming Zou, Xi Yang, Qiuhua Wang, Changjun Nie, Chaorui Tang, Ning Tang, Lanlan Geng, Hanhan Chen, James E Vince, Hirokazu Kanegane, Xiaodong Zhao, Huifang Xian, Wenhao Zhou, Min Zhi, Yuxia Zhang, Zhanghua Chen","doi":"10.1002/mco2.70745","DOIUrl":"https://doi.org/10.1002/mco2.70745","url":null,"abstract":"<p><p>A substantial proportion of patients with X‑-linked inhibitor of apoptosis (XIAP) deficiency develop severe and treatment‑-refractory Crohn's disease (CD). Although hematopoietic stem cell transplantation (HSCT) remains the only curative option for these patients, its outcomes are suboptimal, with a long‑-term survival rate of only 50%. Therefore, identifying novel therapeutic targets is crucial to bridge this unmet clinical need. Here, we demonstrate that the abundance of tuft cells is reduced in both XIAP-deficient CD patients and <i>Xiap</i> knockout (<i>Xiap</i> <sup>-/-</sup>) mice. Mechanistically, XIAP deficiency reduces TLE4 ubiquitination, resulting in elevated TLE4 protein levels and consequent suppression of Wnt/β‑-catenin-ASCL2 signaling, which is critical for secretory lineage differentiation. Tuft cell deficiency may increase susceptibility to microbial dysregulation, thereby promoting intestinal inflammation. Furthermore, we demonstrate that JAK inhibition promotes tuft cell regeneration and ameliorates mucosal inflammation in <i>Xiap</i> <sup>-/-</sup> mice. Consistently, in an XIAP‑-deficient CD patient, treatment with a selective JAK1 inhibitor effectively increased tuft cell proportion and alleviated colonic symptoms. In conclusion, our study identifies tuft cell deficiency as a trigger of intestinal pathology in XIAP‑-deficient Crohn's disease and suggests JAK inhibition as a promising therapeutic strategy.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70745"},"PeriodicalIF":10.7,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793539","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}
MedCommPub Date : 2026-04-23eCollection Date: 2026-05-01DOI: 10.1002/mco2.70744
Mengzhen Lai, Jiaying Chen, Ye Qin, Hui Zhang, Zilu Pan, Tao Zhang, Linjiang Tong, Haotian Tang, Gang Bai, Qiupei Liu, Yan Li, Fang Feng, Peiran Song, Yingqiang Liu, Yi Chen, Yan Fang, Bencan Tang, Meiyu Geng, Ker Yu, Hao Chen, Jian Ding, Hua Xie
{"title":"Sphingosine-1-Phosphate Receptor 3 Confers Tumor Metastasis in Lung Cancer Resistant to Third-Generation EGFR Inhibitor.","authors":"Mengzhen Lai, Jiaying Chen, Ye Qin, Hui Zhang, Zilu Pan, Tao Zhang, Linjiang Tong, Haotian Tang, Gang Bai, Qiupei Liu, Yan Li, Fang Feng, Peiran Song, Yingqiang Liu, Yi Chen, Yan Fang, Bencan Tang, Meiyu Geng, Ker Yu, Hao Chen, Jian Ding, Hua Xie","doi":"10.1002/mco2.70744","DOIUrl":"https://doi.org/10.1002/mco2.70744","url":null,"abstract":"<p><p>The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has significantly improved the survival in EGFR-mutant lung cancer patients. Our team developed limertinib (ASK120067), a novel third-generation EGFR inhibitor with remarkable antitumor effects, which has been launched in China. Despite initial therapeutic responses, EGFR TKIs-treated patients ultimately experience fatal metastatic recurrence and disease progression. However, the underlying mechanism of driving metastasis remains poorly understood. Here, we aim to investigate the pro-metastatic mechanism following treatment with third-generation EGFR TKIs. Transcriptomics analyses of EGFR TKI-resistant tumor models revealed an aberrant upregulation of S1PR3, which conferred enhanced metastatic potential to lung cancer. S1PR3 inhibition dramatically reduced metastasis in resistant cells, while its overexpression potentiated metastatic abilities in parental cells. Notably, S1PR3 was highly enriched in clinical samples with AZD9291 resistance and correlates with poor prognosis. Mechanistically, we found that S1PR3 upregulated RAC1-GTP expression to activate PAK1, thereby promoting epithelial-mesenchymal transition (EMT) and enhancing metastatic capacity of resistant cells. Further studies identified that the overexpression of fibroblast growth factor receptor 1 (FGFR1) increased S1PR3 expression through signal transducer and activator of transcription 4 (STAT4) to promote the emergence of metastatic-resistant cells. Importantly, targeting S1PR3 or FGFR1 blocks metastasis in EGFR TKI-resistant models.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"7 ","pages":"e70744"},"PeriodicalIF":10.7,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13106892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793467","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
