Pub Date : 2025-11-01Epub Date: 2025-10-13DOI: 10.1038/s44321-025-00320-5
Bauke V Schomakers, Adriana S Passadouro, Maria M Trętowicz, Pelle J Simpson, Yorrick R J Jaspers, Michel van Weeghel, Iman Man Hu, Cathelijne M E Lamboo, Denise Cloutier, Barry J Byrne, Jan Bert van Klinken, Paul M L Janssen, Sander R Piersma, Connie R Jimenez, Frédéric M Vaz, Gajja S Salomons, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard
Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.
{"title":"Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.","authors":"Bauke V Schomakers, Adriana S Passadouro, Maria M Trętowicz, Pelle J Simpson, Yorrick R J Jaspers, Michel van Weeghel, Iman Man Hu, Cathelijne M E Lamboo, Denise Cloutier, Barry J Byrne, Jan Bert van Klinken, Paul M L Janssen, Sander R Piersma, Connie R Jimenez, Frédéric M Vaz, Gajja S Salomons, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard","doi":"10.1038/s44321-025-00320-5","DOIUrl":"10.1038/s44321-025-00320-5","url":null,"abstract":"<p><p>Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3227-3246"},"PeriodicalIF":8.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12603102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285785","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}
Pub Date : 2025-10-31DOI: 10.1038/s44321-025-00331-2
Irene Molina Panadero,Antonio Moreno Rodríguez,Angela Rey Hidalgo,Mercedes de la Cruz,Pilar Sánchez,Laura Tomás Gallardo,Thanadon Samernate,Milan Sencanski,Sanja Glisic,Olga Genilloud,Poochit Nonejuie,Antonio J Pérez-Pulido,Abdelkrim Hmadcha,Younes Smani
High-throughput screening studies provide an additional approach to discovering repurposed drugs for antimicrobial treatments. In this work, we report the identification of ENOblock, an anticancer drug, as an antimicrobial agent. We computationally and experimentally validated that ENOblock synergizes with colistin, the last resort antibiotic. Additionally, we identified enolase as the potential bacterial target for ENOblock. The in silico and in vitro antibacterial activity of ENOblock translated into potent in vivo efficacy in an animal infection model. Collectively, the preclinical data support the selection of ENOblock as a promising candidate for antimicrobial development, with the potential to address the urgent threat of infections caused by Acinetobacter baumannii.
{"title":"ENOblock synergizes with colistin to treat Acinetobacter baumannii infections.","authors":"Irene Molina Panadero,Antonio Moreno Rodríguez,Angela Rey Hidalgo,Mercedes de la Cruz,Pilar Sánchez,Laura Tomás Gallardo,Thanadon Samernate,Milan Sencanski,Sanja Glisic,Olga Genilloud,Poochit Nonejuie,Antonio J Pérez-Pulido,Abdelkrim Hmadcha,Younes Smani","doi":"10.1038/s44321-025-00331-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00331-2","url":null,"abstract":"High-throughput screening studies provide an additional approach to discovering repurposed drugs for antimicrobial treatments. In this work, we report the identification of ENOblock, an anticancer drug, as an antimicrobial agent. We computationally and experimentally validated that ENOblock synergizes with colistin, the last resort antibiotic. Additionally, we identified enolase as the potential bacterial target for ENOblock. The in silico and in vitro antibacterial activity of ENOblock translated into potent in vivo efficacy in an animal infection model. Collectively, the preclinical data support the selection of ENOblock as a promising candidate for antimicrobial development, with the potential to address the urgent threat of infections caused by Acinetobacter baumannii.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"71 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411541","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}
Pub Date : 2025-10-30DOI: 10.1038/s44321-025-00329-w
Juan Ignacio Jiménez-Loygorri,Peng Shang,Ibrahim Bayramoglu,Raquel Gómez-Sintes,Adrián Martín-Segura,Helena Ambrosino,Johnson Hoang,Antonio Díaz,Zhaohui Geng,Evripidis Gavathiotis,James R Dutton,Jörn Dengjel,Ana Maria Cuervo,Deborah A Ferrington,Patricia Boya
Autophagy is one of the main intracellular recycling systems and its impairment is considered a primary hallmark of the aging process. Defective macroautophagy in the retinal pigment epithelium (RPE) has been described in age-related macular degeneration (AMD), a blindness-causing disease that affects roughly 200 million patients worldwide. The relevance of chaperone-mediated autophagy (CMA), a selective type of autophagy for proteins containing a KFERQ-like motif, in RPE cell biology and homeostasis remains to be elucidated. Here we describe decreased CMA activity in the RPE of AMD patients compared to healthy age-matched controls, along with accumulation of substrate proteins, and in donor-derived iPSC-RPE cells, which we used to further characterize AMD-associated alterations of cellular homeostasis derived from proteotoxicity. Treatment with CA77.1 (CMA activator) restores proteostasis and remodels specific subsets of the proteome in cells from healthy and AMD donors. CA77.1-treated AMD iPSC-RPE display reduced oxidative stress and improved mitochondrial function. These findings may explain the specific vulnerability of the RPE during AMD and shed light on CMA as a new druggable target for this as-of-now incurable disease.
{"title":"Defective chaperone-mediated autophagy in the retinal pigment epithelium of age-related macular degeneration patients.","authors":"Juan Ignacio Jiménez-Loygorri,Peng Shang,Ibrahim Bayramoglu,Raquel Gómez-Sintes,Adrián Martín-Segura,Helena Ambrosino,Johnson Hoang,Antonio Díaz,Zhaohui Geng,Evripidis Gavathiotis,James R Dutton,Jörn Dengjel,Ana Maria Cuervo,Deborah A Ferrington,Patricia Boya","doi":"10.1038/s44321-025-00329-w","DOIUrl":"https://doi.org/10.1038/s44321-025-00329-w","url":null,"abstract":"Autophagy is one of the main intracellular recycling systems and its impairment is considered a primary hallmark of the aging process. Defective macroautophagy in the retinal pigment epithelium (RPE) has been described in age-related macular degeneration (AMD), a blindness-causing disease that affects roughly 200 million patients worldwide. The relevance of chaperone-mediated autophagy (CMA), a selective type of autophagy for proteins containing a KFERQ-like motif, in RPE cell biology and homeostasis remains to be elucidated. Here we describe decreased CMA activity in the RPE of AMD patients compared to healthy age-matched controls, along with accumulation of substrate proteins, and in donor-derived iPSC-RPE cells, which we used to further characterize AMD-associated alterations of cellular homeostasis derived from proteotoxicity. Treatment with CA77.1 (CMA activator) restores proteostasis and remodels specific subsets of the proteome in cells from healthy and AMD donors. CA77.1-treated AMD iPSC-RPE display reduced oxidative stress and improved mitochondrial function. These findings may explain the specific vulnerability of the RPE during AMD and shed light on CMA as a new druggable target for this as-of-now incurable disease.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"27 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403881","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}
The role of zinc finger protein 334 (ZNF334) in immunological processes remains unknown. We identified a ZNF334 truncation mutation (p.Thr399fs) in a rare case of late-onset cold-induced autoinflammatory disease with elevated TNF-α, IL-1β, IL-6, and extracellular heat shock protein 90 (eHsp90) plasma levels and progressive sensorineural hearing loss. Using patient-derived monocytes and CRISPR/Cas9-edited THP-1 monocytes with a ZNF334 truncation mutation, we discovered that the mutation reduced the interaction between ZNF334 and Hsp90, diminished the endogenous levels of the cold stress regulators Hsp90 and transient receptor potential melastatin 8 (TRPM8), disrupted ER protein folding response and redox homeostasis, and increased cold-induced NF-κB activation and secretion of the proinflammatory TRPM8+ mitochondria-containing extracellular vesicles in monocytes. Long-term cold avoidance alleviated the patient's cold-induced symptoms. In addition, treatment of ZNF334-truncated THP-1 cells with an Hsp90 inhibitor prevented cold-induced TNF and NLRP3 upregulations. Our findings suggest ZNF334 as an essential regulator of cold-induced inflammation and oxidative stress, and Hsp90 ATPase inhibitors might be effective in the treatment of autoinflammatory diseases induced by repeated mild cold exposure.
{"title":"ZNF334 truncation mutation drives cold-induced autoinflammation.","authors":"Joung-Liang Lan,Shih-Hsin Chang,Yi-Hua Lai,Ju-Pi Li,Guan-Jun Chen,Yen-Ju Lin,Ya-Ling Huang,Bor-Luen Chiang,Jan-Gowth Chang,Guan-Yun Lu,Tung-Lin Tsai,Chien-Yu Lin,John Wang,Yi-Chuan Li,Mien-Chie Hung,Chin-An Yang","doi":"10.1038/s44321-025-00328-x","DOIUrl":"https://doi.org/10.1038/s44321-025-00328-x","url":null,"abstract":"The role of zinc finger protein 334 (ZNF334) in immunological processes remains unknown. We identified a ZNF334 truncation mutation (p.Thr399fs) in a rare case of late-onset cold-induced autoinflammatory disease with elevated TNF-α, IL-1β, IL-6, and extracellular heat shock protein 90 (eHsp90) plasma levels and progressive sensorineural hearing loss. Using patient-derived monocytes and CRISPR/Cas9-edited THP-1 monocytes with a ZNF334 truncation mutation, we discovered that the mutation reduced the interaction between ZNF334 and Hsp90, diminished the endogenous levels of the cold stress regulators Hsp90 and transient receptor potential melastatin 8 (TRPM8), disrupted ER protein folding response and redox homeostasis, and increased cold-induced NF-κB activation and secretion of the proinflammatory TRPM8+ mitochondria-containing extracellular vesicles in monocytes. Long-term cold avoidance alleviated the patient's cold-induced symptoms. In addition, treatment of ZNF334-truncated THP-1 cells with an Hsp90 inhibitor prevented cold-induced TNF and NLRP3 upregulations. Our findings suggest ZNF334 as an essential regulator of cold-induced inflammation and oxidative stress, and Hsp90 ATPase inhibitors might be effective in the treatment of autoinflammatory diseases induced by repeated mild cold exposure.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"19 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403833","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}
Early detection of gastric cancer (GC) is critical for improving prognosis, yet conventional biomarkers lack sensitivity and specificity, necessitating non-invasive, high-performance diagnostic tools. This study integrated untargeted metabolomics and machine learning to develop a plasma metabolite panel for GC diagnosis and mechanistic insights. Plasma and tissue samples from two cohorts (n = 597) were analyzed using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). A six-metabolite panel was identified and validated, demonstrating excellent diagnostic performance (area under the curve: 0.947-0.982 in discovery; 0.920-0.951 in validation) and superior sensitivity (0.900-0.940) compared to conventional markers (0.020-0.240). Isovalerylcarnitine (C5), a key component, was consistently downregulated in both plasma and tissue samples. Mendelian randomization supported a causal relationship between isovalerylcarnitine (C5) and GC risk. Proteomic analyses revealed inverse correlations between C5 and cadherin/MMP family proteins. Functional assays confirmed that isovalerylcarnitine (C5) inhibited GC cell migration and invasion via calpain-mediated cleavage of VE-cadherin and MMP2. This study identifies a robust diagnostic metabolite panel for GC detection and highlights a novel mechanistic role of isovalerylcarnitine (C5) in GC progression, supporting its utility as both a biomarker and therapeutic target.
{"title":"Metabolic signatures for gastric cancer diagnosis and mechanistic insights: a multicenter study.","authors":"Juan Zhu,Yida Huang,Xue Li,Bin Liu,Li Yuan,Le Wang,Kun Qian,Yingying Mao,Yongjie Xu,Lingbin Du,Xiangdong Cheng","doi":"10.1038/s44321-025-00325-0","DOIUrl":"https://doi.org/10.1038/s44321-025-00325-0","url":null,"abstract":"Early detection of gastric cancer (GC) is critical for improving prognosis, yet conventional biomarkers lack sensitivity and specificity, necessitating non-invasive, high-performance diagnostic tools. This study integrated untargeted metabolomics and machine learning to develop a plasma metabolite panel for GC diagnosis and mechanistic insights. Plasma and tissue samples from two cohorts (n = 597) were analyzed using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). A six-metabolite panel was identified and validated, demonstrating excellent diagnostic performance (area under the curve: 0.947-0.982 in discovery; 0.920-0.951 in validation) and superior sensitivity (0.900-0.940) compared to conventional markers (0.020-0.240). Isovalerylcarnitine (C5), a key component, was consistently downregulated in both plasma and tissue samples. Mendelian randomization supported a causal relationship between isovalerylcarnitine (C5) and GC risk. Proteomic analyses revealed inverse correlations between C5 and cadherin/MMP family proteins. Functional assays confirmed that isovalerylcarnitine (C5) inhibited GC cell migration and invasion via calpain-mediated cleavage of VE-cadherin and MMP2. This study identifies a robust diagnostic metabolite panel for GC detection and highlights a novel mechanistic role of isovalerylcarnitine (C5) in GC progression, supporting its utility as both a biomarker and therapeutic target.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"6 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373639","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}
Characterization of primary immune dysregulations and deficiency disorders caused by hyperactivating variants of the JAK/STAT pathway highlighted its crucial role in immune cell development and response. To systematically evaluate pathogenic JAK1 variants, we developed a structure-based predictive framework adapting AlphaFold2, modeling both the active and inactive conformations of JAK1. Dual-state modeling of 21,926 JAK1 variants enabled discrimination between pathogenic and benign variants based on their impact on regulatory conformation. Applying this approach to a large cohort of patients with suspected primary immune dysregulation and deficiency led to the identification of five novel variants located in key cis-regulatory and catalytic domains, with predicted gain of function activity. Ectopic expression of these variants in cell line resulted in varying levels of hyperactivation of JAK1 and multiple STATs at baseline. Furthermore, treatment of two patients with Tofacitinib suppressed JAK1 hyperactivation, normalized plasma cytokine levels and interferon signatures, and significantly improved clinical symptoms. These findings reveal diverse mechanisms of JAK1 gain of function, expanding the clinical spectrum JAK1 GOF, and underscore the importance of precise variant characterization for effective personalized therapy.
{"title":"In silico modeling guides identification of novel JAK1 variants associated with immune dysregulation.","authors":"Marie Jeanpierre,Orianne Debeaupuis,Camille Brunaud,Judith Yancoski,Quentin Riller,Jerome Hadjadj,Marie-Claude Stolzenberg,Giselle Villarreal,Marie Martha Katsicas,Mariana Villa,Joao Farela Neves,Jean-Louis Stephan,Cédric Léonard,Estibaliz Lazaro,Jonathan Ciron,Charlotte Boussard,Fabienne Mazerolles,Aude Magerus,Pelle Olivier,Cecile Masson,Yohann Schmitt,Benedicte Hoareau,Angélique Vinit,Bénédicte Neven,Pierre Quartier,Herve Isambert,Matías Oleastro,Silvia Danielian,Marianna Parlato,Frederic Rieux-Laucat","doi":"10.1038/s44321-025-00317-0","DOIUrl":"https://doi.org/10.1038/s44321-025-00317-0","url":null,"abstract":"Characterization of primary immune dysregulations and deficiency disorders caused by hyperactivating variants of the JAK/STAT pathway highlighted its crucial role in immune cell development and response. To systematically evaluate pathogenic JAK1 variants, we developed a structure-based predictive framework adapting AlphaFold2, modeling both the active and inactive conformations of JAK1. Dual-state modeling of 21,926 JAK1 variants enabled discrimination between pathogenic and benign variants based on their impact on regulatory conformation. Applying this approach to a large cohort of patients with suspected primary immune dysregulation and deficiency led to the identification of five novel variants located in key cis-regulatory and catalytic domains, with predicted gain of function activity. Ectopic expression of these variants in cell line resulted in varying levels of hyperactivation of JAK1 and multiple STATs at baseline. Furthermore, treatment of two patients with Tofacitinib suppressed JAK1 hyperactivation, normalized plasma cytokine levels and interferon signatures, and significantly improved clinical symptoms. These findings reveal diverse mechanisms of JAK1 gain of function, expanding the clinical spectrum JAK1 GOF, and underscore the importance of precise variant characterization for effective personalized therapy.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"29 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357848","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}
Pub Date : 2025-10-23DOI: 10.1038/s44321-025-00321-4
Aigerim Aidarova,Marieke Carels,Mira Haegman,Yasmine Driege,Steven Timmermans,Eline Van Damme,Javier Aguilera-Lizarraga,Maria Francesca Viola,Rita de Cássia Collaço,Joan Manils,Steven C Ley,Frank Bosmans,Tom Van de Wiele,Guy Boeckxstaens,Claude Libert,Rudi Beyaert,Inna S Afonina
CARD14 is an intracellular NF-κB signaling mediator in the skin, and rare CARD14 variants have been associated with psoriasis and atopic dermatitis. CARD14 is also expressed in intestinal epithelial cells (IEC). However, its function in the intestine remains unknown. We demonstrate here that transgenic mice expressing the psoriasis-associated gain-of-function human CARD14(E138A) mutant specifically in IEC show mild intestinal inflammation, without epithelial damage. Moreover, CARD14(E138A)IEC mice show a drastic reduction in intestinal motility, often associated with rectal prolapse. Enteric neuronal survival and functionality are unaffected in CARD14(E138A)IEC mice. Transcriptome analysis of IEC from CARD14(E138A)IEC mice reveals decreased expression of antimicrobial peptides by Paneth cells, accompanied by microbial dysbiosis and increased susceptibility to enteric bacterial infection. Our findings suggest that gain-of-function CARD14 mutations may not only predispose patients to psoriasis but also mild intestinal inflammation, reduced intestinal motility, and increased sensitivity to intestinal infection. CARD14(E138A)IEC mice are also a valuable tool for further investigation of IEC-intrinsic molecular processes involved in intestinal inflammation and motility disorders.
{"title":"CARD14 signaling in intestinal epithelial cells induces intestinal inflammation and intestinal transit delay.","authors":"Aigerim Aidarova,Marieke Carels,Mira Haegman,Yasmine Driege,Steven Timmermans,Eline Van Damme,Javier Aguilera-Lizarraga,Maria Francesca Viola,Rita de Cássia Collaço,Joan Manils,Steven C Ley,Frank Bosmans,Tom Van de Wiele,Guy Boeckxstaens,Claude Libert,Rudi Beyaert,Inna S Afonina","doi":"10.1038/s44321-025-00321-4","DOIUrl":"https://doi.org/10.1038/s44321-025-00321-4","url":null,"abstract":"CARD14 is an intracellular NF-κB signaling mediator in the skin, and rare CARD14 variants have been associated with psoriasis and atopic dermatitis. CARD14 is also expressed in intestinal epithelial cells (IEC). However, its function in the intestine remains unknown. We demonstrate here that transgenic mice expressing the psoriasis-associated gain-of-function human CARD14(E138A) mutant specifically in IEC show mild intestinal inflammation, without epithelial damage. Moreover, CARD14(E138A)IEC mice show a drastic reduction in intestinal motility, often associated with rectal prolapse. Enteric neuronal survival and functionality are unaffected in CARD14(E138A)IEC mice. Transcriptome analysis of IEC from CARD14(E138A)IEC mice reveals decreased expression of antimicrobial peptides by Paneth cells, accompanied by microbial dysbiosis and increased susceptibility to enteric bacterial infection. Our findings suggest that gain-of-function CARD14 mutations may not only predispose patients to psoriasis but also mild intestinal inflammation, reduced intestinal motility, and increased sensitivity to intestinal infection. CARD14(E138A)IEC mice are also a valuable tool for further investigation of IEC-intrinsic molecular processes involved in intestinal inflammation and motility disorders.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351767","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}
Pub Date : 2025-10-21DOI: 10.1038/s44321-025-00322-3
Smriti Parashar,Mohammad Oliaeimotlagh,Payel Roy,Qingkang Lyu,Anusha Bellapu,Mikhail Fomin,Sunil Kumar,Yan Wang,Chantel C McSkimming,Coleen A McNamara,Klaus Ley
Under conditions of chronic unresolved inflammation characteristic of atherosclerosis, regulatory CD4+ T cells (Tregs) become unstable and convert to cytotoxic exTregs. The mechanism driving this conversion in humans is unclear. Here, we show unresolved endoplasmic reticulum (ER) stress as a key factor driving Treg instability. Human exTregs undergo ER stress and consequent mitochondrial dysfunction that remains unchecked due to defective mitophagy. Integrated stress response (ISR), a pathway that can trigger inflammatory signaling, is also upregulated in exTregs. exTregs are highly apoptotic and are more susceptible to stress-mediated cellular dysfunction due to their senescent state. In a phenotype reminiscent of exTregs, Tregs from coronary artery disease (CAD) patients show high ER stress and mitochondrial depolarization. This is further exacerbated in CD4+ T cells residing in atherosclerotic plaques. Pro-atherosclerotic stressors such as oxLDL and interferon-γ induce ER stress and mitochondrial dysfunction in Tregs in vitro. We conclude that the maladaptive inflammatory environment in atherosclerosis triggers ER stress and mitochondrial dysfunction, contributing to Treg instability in CAD.
{"title":"ER stress induced mitochondrial dysfunction drives Treg instability in coronary artery disease.","authors":"Smriti Parashar,Mohammad Oliaeimotlagh,Payel Roy,Qingkang Lyu,Anusha Bellapu,Mikhail Fomin,Sunil Kumar,Yan Wang,Chantel C McSkimming,Coleen A McNamara,Klaus Ley","doi":"10.1038/s44321-025-00322-3","DOIUrl":"https://doi.org/10.1038/s44321-025-00322-3","url":null,"abstract":"Under conditions of chronic unresolved inflammation characteristic of atherosclerosis, regulatory CD4+ T cells (Tregs) become unstable and convert to cytotoxic exTregs. The mechanism driving this conversion in humans is unclear. Here, we show unresolved endoplasmic reticulum (ER) stress as a key factor driving Treg instability. Human exTregs undergo ER stress and consequent mitochondrial dysfunction that remains unchecked due to defective mitophagy. Integrated stress response (ISR), a pathway that can trigger inflammatory signaling, is also upregulated in exTregs. exTregs are highly apoptotic and are more susceptible to stress-mediated cellular dysfunction due to their senescent state. In a phenotype reminiscent of exTregs, Tregs from coronary artery disease (CAD) patients show high ER stress and mitochondrial depolarization. This is further exacerbated in CD4+ T cells residing in atherosclerotic plaques. Pro-atherosclerotic stressors such as oxLDL and interferon-γ induce ER stress and mitochondrial dysfunction in Tregs in vitro. We conclude that the maladaptive inflammatory environment in atherosclerosis triggers ER stress and mitochondrial dysfunction, contributing to Treg instability in CAD.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"19 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338684","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}
Pub Date : 2025-10-15DOI: 10.1038/s44321-025-00323-2
Ang Li,Sen Huang,Shu-Qin Cao,Jinyi Lin,Linping Zhao,Feng Yu,Miaodan Huang,Lele Yang,Jiaqi Xin,Jing Wen,Lingli Yan,Ke Zhang,Maoyuan Jiang,Weidong Le,Peng Li,Yong U Liu,Dajiang Qin,Jiahong Lu,Guang Lu,Hanming Shen,Xiaoli Yao,Evandro F Fang,Huanxing Su
Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.
{"title":"Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.","authors":"Ang Li,Sen Huang,Shu-Qin Cao,Jinyi Lin,Linping Zhao,Feng Yu,Miaodan Huang,Lele Yang,Jiaqi Xin,Jing Wen,Lingli Yan,Ke Zhang,Maoyuan Jiang,Weidong Le,Peng Li,Yong U Liu,Dajiang Qin,Jiahong Lu,Guang Lu,Hanming Shen,Xiaoli Yao,Evandro F Fang,Huanxing Su","doi":"10.1038/s44321-025-00323-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00323-2","url":null,"abstract":"Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"64 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296052","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}
Pub Date : 2025-10-13DOI: 10.1038/s44321-025-00315-2
Yi Xiong,Fang Zeng,Kaiping Luo,Li Wang,Manna Li,Yanxia Chen,Tianlun Huang,Chengyun Xu,Gaosi Xu,Honghong Zou
The proliferation of glomerular mesangial cells is a fundamental pathological change in immunoglobulin A nephropathy (IgAN). This study aims to elucidate the mechanisms that affect the proliferation of glomerular mesangial cells. Bioinformatics analysis combined with clinical detection identified the key molecule glycine decarboxylase (GLDC). In vitro experiments revealed that GLDC knockdown reduces the proliferative effect of pIgA on mesangial cells. Pyrimidine metabolism is involved in the proliferation regulation of mesangial cells by GLDC. Additionally, GLDC's regulation of glycolysis in mesangial cells was discovered, which further affects the progression of renal fibrosis and the proliferation of glomerular mesangial cells. Upon knockdown of the key rate-limiting enzymes of pyrimidine metabolism, CAD and DHODH, the overexpression of GLDC lost its regulatory effect on glycolysis. The regulatory mechanisms described above were confirmed by inhibiting GLDC expression in the kidneys in vivo. In conclusion, GLDC upregulates pyrimidine metabolic flux, which subsequently fuels glycolysis to promote mesangial cell proliferation, promoting IgAN progression.
{"title":"Glycine decarboxylase advances IgA nephropathy by boosting mesangial cell proliferation through the pyrimidine pathway.","authors":"Yi Xiong,Fang Zeng,Kaiping Luo,Li Wang,Manna Li,Yanxia Chen,Tianlun Huang,Chengyun Xu,Gaosi Xu,Honghong Zou","doi":"10.1038/s44321-025-00315-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00315-2","url":null,"abstract":"The proliferation of glomerular mesangial cells is a fundamental pathological change in immunoglobulin A nephropathy (IgAN). This study aims to elucidate the mechanisms that affect the proliferation of glomerular mesangial cells. Bioinformatics analysis combined with clinical detection identified the key molecule glycine decarboxylase (GLDC). In vitro experiments revealed that GLDC knockdown reduces the proliferative effect of pIgA on mesangial cells. Pyrimidine metabolism is involved in the proliferation regulation of mesangial cells by GLDC. Additionally, GLDC's regulation of glycolysis in mesangial cells was discovered, which further affects the progression of renal fibrosis and the proliferation of glomerular mesangial cells. Upon knockdown of the key rate-limiting enzymes of pyrimidine metabolism, CAD and DHODH, the overexpression of GLDC lost its regulatory effect on glycolysis. The regulatory mechanisms described above were confirmed by inhibiting GLDC expression in the kidneys in vivo. In conclusion, GLDC upregulates pyrimidine metabolic flux, which subsequently fuels glycolysis to promote mesangial cell proliferation, promoting IgAN progression.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283453","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}
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