EMBO Molecular Medicine最新文献

{"title":"Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer.","authors":"Mericka McCabe, Rajanya Bhattacharyya, Rebecca Sereda, Olaya Santiago-Fernández, Rabia R Khawaja, Antonio Diaz, Kristen Lindenau, Deniz Gulfem Ozturk, Thomas P Garner, Simone Sidoli, Ana Maria Cuervo, Evripidis Gavathiotis","doi":"10.1038/s44321-025-00254-y","DOIUrl":"10.1038/s44321-025-00254-y","url":null,"abstract":"<p><p>Chaperone-mediated autophagy (CMA), a type of selective degradation of cytosolic proteins in lysosomes, is commonly upregulated in cancer cells, contributing to their survival and growth. The lack of a specific target for CMA inhibition has limited CMA blockage to genetic manipulations or global lysosomal function inhibition. Here, using genetic modulation, transcriptional analysis, and functional studies, we demonstrate a regulatory role for the interaction of the retinoic acid receptor alpha (RARα) and its corepressor, the nuclear receptor corepressor 1 (NCoR1), on CMA in non-small cell lung cancer (NSCLC). By targeting the disruption of the NCoR1/RARα complex with a structure-based screening strategy, we identified compound CIM7, a potent and selective CMA inhibitor that has no effect on macroautophagy. CIM7 preferentially inhibits CMA in NSCLC cells over normal cells, reduces tumor growth in NSCLC cells, and demonstrates efficacy in an in vivo xenograft mouse model with no observed toxicity in blood or major tissues. These findings reveal a druggable mechanism for selective CMA inhibition and a first-in-class CMA inhibitor as a potential therapeutic strategy for NSCLC.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1716-1755"},"PeriodicalIF":9.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A protein-based classifier for differentiating follicular thyroid adenoma and carcinoma.","authors":"Yaoting Sun, He Wang, Lu Li, Jianbiao Wang, Wanyuan Chen, Li Peng, Pingping Hu, Jing Yu, Xue Cai, Nan Yao, Yan Zhou, Jiatong Wang, Yingrui Wang, Liqin Qian, Weigang Ge, Mengni Chen, Feng Yang, Zhiqiang Gui, Wei Sun, Zhihong Wang, Minghua Ge, Yi He, Guangzhi Wang, Yongfu Zhao, Huanjie Chen, Xiaohong Wu, Yuxin Du, Wenjun Wei, Fan Wu, Dingcun Luo, Xiangfeng Lin, Haitao Zheng, Xin Zhu, Bei Wei, Jiafei Shen, Jincao Yao, Zhennan Yuan, Tong Liu, Jun Pan, Yifeng Zhang, Yangfan Lv, Qiaonan Guo, Qijun Wu, Tingting Gong, Ting Chen, Shu Zheng, Jingqiang Zhu, Hanqing Liu, Chuang Chen, Hong Han, Sathiyamoorthy Selvarajan, Michael Mingzhao Xing, Kennichi Kakudo, Erik K Alexander, Yijun Wu, Yu Wang, Dong Xu, Hao Zhang, Xiu Nie, Oi Lian Kon, N Gopalakrishna Iyer, Zhiyan Liu, Yi Zhu, Haixia Guan, Tiannan Guo","doi":"10.1038/s44321-025-00242-2","DOIUrl":"10.1038/s44321-025-00242-2","url":null,"abstract":"<p><p>Differentiating follicular thyroid adenoma (FTA) from carcinoma (FTC) remains challenging due to similar histological features separate from invasion. This study developed and validated DNA- and/or protein-based classifiers. A total of 2443 thyroid samples from 1568 patients were obtained from 24 centers in China and Singapore. Next-generation sequencing of a 66-gene panel revealed 41 (62.1%) detectable genes, while 25 were not, showing similar alteration patterns with differing mutation frequencies. Proteomics quantified 10,336 proteins, with 187 dysregulated. A discovery protein-based XGBoost model achieved an AUROC of 0.899 (95% CI, 0.849-0.949), outperforming the gene-based model (AUROC 0.670 [95% CI, 0.612-0.729]). A subsequent 24-protein classifier, developed via targeted mass spectrometry and validated in three independent sets, showed high performance in retrospective cohorts (AUROC 0.871 [95% CI, 0.833-0.910] and 0.853 [95% CI, 0.772-0.934]) and prospective biopsies (AUROC 0.781 [95% CI, 0.563-1.000]). It exhibited a 95.7% negative predictive value for ruling out malignancy. This study presents a promising protein-based approach for the differential diagnosis of FTA and FTC, potentially enhancing diagnostic accuracy and clinical decision-making.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1519-1538"},"PeriodicalIF":9.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan.","authors":"Lucas Schoenfeldt, Patrick T Paine, Sara Picó, Nibrasul H Kamaludeen M, Grace B Phelps, Calida Mrabti, Gabriela Desdín-Micó, María Del Carmen Maza, Kevin Perez, Alejandro Ocampo","doi":"10.1038/s44321-025-00265-9","DOIUrl":"https://doi.org/10.1038/s44321-025-00265-9","url":null,"abstract":"<p><p>The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown. Here, we demonstrated that chemical-induced partial reprogramming can improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan and healthspan. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical-induced partial reprogramming, opening a path towards future translational applications.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay between fungal infections and autoimmunity: mechanisms and therapeutic perspectives.","authors":"Devon T DiPalma,Miranda K Lumbreras,Mari L Shinohara","doi":"10.1038/s44321-025-00262-y","DOIUrl":"https://doi.org/10.1038/s44321-025-00262-y","url":null,"abstract":"Fungal infections and autoimmunity share a complex, bidirectional relationship that significantly impacts patient outcomes. Emerging evidence highlights how fungal pathogens contribute to autoimmune processes by triggering immune dysregulation. Conversely, autoimmunity and its immunomodulatory treatments increase susceptibility to fungal infections. These interactions manifest through altered immune responses, including changes in inflammatory signaling, antigen recognition, and mycobiome composition. The resulting interplay complicates disease management, necessitating careful balancing of antifungal defenses with immune modulation. This review synthesizes current knowledge on the role of fungal infections in the progression of autoimmune conditions and explores how autoimmune diseases predispose individuals to fungal infections. Key insights emphasize the need for integrative treatment approaches, addressing both infection risks and immune system imbalances.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"8 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reelin-LRP8 signaling mediates brain dissemination of breast cancer cells via abluminal migration.","authors":"Haofeng Huang, Min Zhang, Enyu Huang, Yongfang Zhao, Xiaoyu Li, Pu Qiu, Cairui Li, Jiahua Tao, Yuanqi Zhang, Lianxiang Luo, Guozhu Ning, Ceshi Chen, Jingjing Zhang","doi":"10.1038/s44321-025-00260-0","DOIUrl":"https://doi.org/10.1038/s44321-025-00260-0","url":null,"abstract":"<p><p>Brain metastasis (BM) remains a significant challenge in breast cancer (BC) management. While conventional metastatic routes primarily involve hematogenous dissemination, emerging evidence suggests that BC cells can also migrate along the abluminal surface of blood vessels, bypassing the blood-brain barrier (BBB). To investigate this phenomenon, we established a zebrafish xenograft model utilizing GFP-labeled MDA-MB-231 cells, allowing real-time observation of BC cell migration along the posterior cerebral veins. Our findings revealed that LRP8, an apolipoprotein E receptor, is upregulated in BC patients with brain metastasis. Functional studies demonstrated that LRP8 knockdown significantly inhibited proliferation, migration, and invasion of triple-negative breast cancer (TNBC) cells both in vitro and in vivo. Mechanistically, LRP8 promotes the activation of CDC42, enhancing filopodia formation and cell motility, a process influenced by the neuronal extracellular matrix protein, Reelin. Furthermore, we demonstrated the therapeutic potential of MEN 10207, a neurokinin-2 receptor antagonist, in inhibiting TNBC cell migration and suppressing BM formation in both zebrafish and mouse models. These findings provide novel insights into the mechanisms underlying extravascular brain dissemination of BC, highlighting the Reelin-LRP8-CDC42 axis as a potential therapeutic target for this devastating complication.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144283012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ki-67 promotes inflammatory signaling governing neutrophil recruitment during respiratory infections.","authors":"Min Yee, Ravi Misra, Sarah Vesecky, Michael Barravecchia, Rauf A Najar, Arshad Rahman, Gloria S Pryhuber, David A Dean, B Paige Lawrence, Daniel Fisher, Michael A O'Reilly","doi":"10.1038/s44321-025-00261-z","DOIUrl":"10.1038/s44321-025-00261-z","url":null,"abstract":"<p><p>Neutrophils defend against respiratory infections but cause acute lung injury (ALI) when excessively recruited to the lung. Early life environmental factors can shape lung development, but how they impact neutrophil recruitment is not known. We show that exposing newborn mice to hyperoxia increases the number of adult alveolar type 1 (AT1) epithelial cells expressing the proliferation marker Ki-67. Although these cells were not proliferating, they expressed high levels of chemokines that stimulated neutrophil recruitment and ALI when mice were infected with influenza A virus or exposed to lipopolysaccharide (LPS). Neutrophil recruitment and chemokine production were attenuated in Ki-67 hypomorph mice infected with virus or exposed to LPS and enhanced by genetically overexpressing Ki-67 in their lungs. Silencing Ki-67 in a mouse AT1-like cell line reduced basal and IL-1β stimulation of RelA/p65 and NF-κB-dependent transcription of the chemokines Cxcl1 and Cxcl5. Our findings reveal a novel role for Ki-67 to modulate the intensity of epithelial pro-inflammatory signaling, controlling neutrophil recruitment. The severity of respiratory infections may be influenced by mitogens and environmental factors that increase the expression of Ki-67.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations.","authors":"Sota Torii, Keiki Nagaharu, Nanako Nakanishi, Hidehito Usui, Yumiko Hori, Katsutoshi Hirose, Satoru Toyosawa, Eiichi Morii, Mitsunaga Narushima, Yoshiaki Kubota, Osamu Nakagawa, Kyoko Imanaka-Yoshida, Kazuaki Maruyama","doi":"10.1038/s44321-025-00235-1","DOIUrl":"10.1038/s44321-025-00235-1","url":null,"abstract":"<p><p>Congenital vascular malformations, affecting 0.5% of the population, often occur in the head and neck, complicating treatment due to the critical functions in these regions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these areas, tracing them to the cardiopharyngeal mesoderm (CPM), which contributes to the development of the head, neck, and cardiovascular system in both mouse and human embryos. In this study, we investigated the pathogenesis of these malformations by expressing Pik3ca^H1047R in the CPM. Mice expressing Pik3ca^H1047R in the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3ca^H1047R upregulates Vegf-a expression in endothelial cells through HIF-mediated hypoxia signaling. Human samples supported these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, inhibition of HIF-1α and VEGF-A in the mouse model significantly reduced abnormal vasculature. These results highlight the role of embryonic origins and hypoxia-driven mechanisms in vascular malformations, providing a foundation for the development of therapies targeting these difficult-to-treat conditions.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1289-1324"},"PeriodicalIF":9.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-synuclein misfolding as fluid biomarker for Parkinson's disease measured with the iRS platform.","authors":"Martin Schuler, Grischa Gerwert, Marvin Mann, Nathalie Woitzik, Lennart Langenhoff, Diana Hubert, Deniz Duman, Adrian Höveler, Sandy Galkowski, Jonas Simon, Robin Denz, Sandrina Weber, Eun-Hae Kwon, Robin Wanka, Carsten Kötting, Jörn Güldenhaupt, Léon Beyer, Lars Tönges, Brit Mollenhauer, Klaus Gerwert","doi":"10.1038/s44321-025-00229-z","DOIUrl":"10.1038/s44321-025-00229-z","url":null,"abstract":"<p><p>Misfolding and aggregation of alpha-synuclein (αSyn) play a key role in the pathophysiology of Parkinson's disease (PD). Despite considerable advances in diagnostics, an early and differential diagnosis of PD still represents a major challenge. We innovated the immuno-infrared sensor (iRS) platform for measuring αSyn misfolding. We analyzed cerebrospinal fluid (CSF) from two cohorts comprising PD cases, atypical Parkinsonian disorders, and disease controls. We obtained an AUC of 0.90 (n = 134, 95% CI 0.85-0.96) for separating PD/MSA from controls by determination of the αSyn misfolding by iRS. Using two thresholds divided individuals as unaffected/affected by misfolding with an intermediate area in between. Comparing the affected/unaffected cases, controls versus PD/MSA cases were classified with 97% sensitivity and 92% specificity. The spectral data revealed misfolding from an α-helical/random-coil αSyn in controls to β-sheet enriched αSyn in PD and MSA cases. Moreover, a first subgroup analysis implied the potential for patient stratification in clinically overlapping cases. The iRS, directly measuring all αSyn conformers, is complementary to the αSyn seed-amplification assays (SAAs), which however only amplify seeding competent conformers.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1203-1221"},"PeriodicalIF":9.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression.","authors":"Sang-Hoon Lee, Hyun-Jun Kim, Seon-Wook Kim, Hyunju Lee, Da-Woon Jung, Darren Reece Williams","doi":"10.1038/s44321-025-00234-2","DOIUrl":"10.1038/s44321-025-00234-2","url":null,"abstract":"<p><p>Skeletal muscle wasting results from numerous conditions, such as sarcopenia, glucocorticoid therapy or intensive care. It prevents independent living in the elderly, predisposes to secondary diseases, and ultimately reduces lifespan. There is no approved drug therapy and the major causative mechanisms are not fully understood. Dual specificity phosphatase 22 (DUSP22) is a pleiotropic signaling molecule that plays important roles in immunity and cancer. However, the role of DUSP22 in skeletal muscle wasting is unknown. In this study, DUSP22 was found to be upregulated in sarcopenia patients and models of skeletal muscle wasting. DUSP22 knockdown or treatment with BML-260 (a small molecule previously reported to target DUSP22) prevented multiple forms of muscle wasting. Mechanistically, targeting DUSP22 suppressed FOXO3a, a master regulator of skeletal muscle wasting, via downregulation of the stress-activated kinase JNK, which occurred independently of aberrant Akt activation. DUSP22 targeting was also effective in human skeletal muscle cells undergoing atrophy. In conclusion, phosphatase DUSP22 is a novel target for preventing skeletal muscle wasting and BML-260 treatment is therapeutically effective. The DUSP22-JNK-FOXO3a axis could be exploited to treat sarcopenia or related aging disorders.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1259-1288"},"PeriodicalIF":9.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-Driven refractory vascular malformations.","authors":"Sota Torii, Keiki Nagaharu, Nanako Nakanishi, Hidehito Usui, Yumiko Hori, Katsutoshi Hirose, Satoru Toyosawa, Eiichi Morii, Mitsunaga Narushima, Yoshiaki Kubota, Osamu Nakagawa, Kyoko Imanaka-Yoshida, Kazuaki Maruyama","doi":"10.1038/s44321-025-00246-y","DOIUrl":"10.1038/s44321-025-00246-y","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1499"},"PeriodicalIF":9.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}