Nature metabolismPub Date : 2026-09-04DOI: 10.1038/s42255-026-01600-1
Antonio Molinaro, Peder Rustøen Braadland, Guido Carpino, Alba Carreras, Marios Nikolaidis, Petra Hanzely, Katharina R Beck, Ahmad H Ali, Lars Bossen, Anna Frank, Annika Lundqvist, Brian D Juran, Diletta Overi, Lei Geng, Enya Amundsen-Isaksen, Henrik Mikael Reims, Ida Björk, Krzysztof Grzyb, Andreas Abildgaard, Trine Folseraas, Martin Cornillet, Hólmfríður Helgadóttir, Bryan M McCauley, Laura Cristoferi, Marco Carbone, Vincenzo Cardinale, Marte L Høivik, Lise Katrine Engesæter, Sara K V Tjønnfjord, Adrian McCann, Per M Ueland, Mette Vesterhus, Tom H Karlsen, Henning Grønbæk, Eugenio Gaudio, Konstantinos N Lazaridis, Annika Bergquist, Espen Melum, Fredrik Bäckhed, Johannes Roksund Hov
{"title":"Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling.","authors":"Antonio Molinaro, Peder Rustøen Braadland, Guido Carpino, Alba Carreras, Marios Nikolaidis, Petra Hanzely, Katharina R Beck, Ahmad H Ali, Lars Bossen, Anna Frank, Annika Lundqvist, Brian D Juran, Diletta Overi, Lei Geng, Enya Amundsen-Isaksen, Henrik Mikael Reims, Ida Björk, Krzysztof Grzyb, Andreas Abildgaard, Trine Folseraas, Martin Cornillet, Hólmfríður Helgadóttir, Bryan M McCauley, Laura Cristoferi, Marco Carbone, Vincenzo Cardinale, Marte L Høivik, Lise Katrine Engesæter, Sara K V Tjønnfjord, Adrian McCann, Per M Ueland, Mette Vesterhus, Tom H Karlsen, Henning Grønbæk, Eugenio Gaudio, Konstantinos N Lazaridis, Annika Bergquist, Espen Melum, Fredrik Bäckhed, Johannes Roksund Hov","doi":"10.1038/s42255-026-01600-1","DOIUrl":"https://doi.org/10.1038/s42255-026-01600-1","url":null,"abstract":"<p><p>Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that can lead to biliary cancer and end-stage liver disease. PSC is associated with inflammatory bowel disease and an altered gut microbiota. However, the molecular mechanisms underlying gut-liver interactions in PSC remain poorly characterized. Here we show that the gut microbiota-derived metabolite imidazole propionate (ImP) is a disease driver in PSC. Individuals with PSC have higher circulating ImP levels than individuals with related conditions, and high ImP levels predict reduced survival in PSC. Cholangiocytes exposed to ImP show activated mammalian target of rapamycin complex 1 (mTORC1) signalling and secrete pro-inflammatory and pro-fibrogenic factors. Chronic administration of ImP to mice induces liver inflammation and fibrosis through a p38-dependent mechanism, upstream of mTORC1. We propose that chronic exposure to ImP induces cholangiocyte injury, which alone or in concert with other factors causes clinical worsening of PSC. Therefore, targeting ImP production or signalling may represent therapeutic avenues in PSC.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891907","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}
Nature metabolismPub Date : 2026-09-04DOI: 10.1038/s42255-026-01604-x
Emily D Madigan, Sandro L Matos, Michael J Jurczak
{"title":"UBE2N flips the switch on for mitophagy and off for MASH.","authors":"Emily D Madigan, Sandro L Matos, Michael J Jurczak","doi":"10.1038/s42255-026-01604-x","DOIUrl":"https://doi.org/10.1038/s42255-026-01604-x","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891943","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}
Nature metabolismPub Date : 2026-09-04DOI: 10.1038/s42255-026-01590-0
Feng Wang, Jin Lee, Jeong-Su Park, Meizhou Huang, Hwan Ma, Guoyan Sui, Zixiong Zhou, Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, Xuefeng Wu, Haram Lee, Soohwan Oh, Hanseul Park, Key-Hwan Lim, Chun-Woong Park, Sang-Bae Han, Jin Tae Hong, Michael Karin, Yoon Seok Roh, Ekihiro Seki
{"title":"UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.","authors":"Feng Wang, Jin Lee, Jeong-Su Park, Meizhou Huang, Hwan Ma, Guoyan Sui, Zixiong Zhou, Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, Xuefeng Wu, Haram Lee, Soohwan Oh, Hanseul Park, Key-Hwan Lim, Chun-Woong Park, Sang-Bae Han, Jin Tae Hong, Michael Karin, Yoon Seok Roh, Ekihiro Seki","doi":"10.1038/s42255-026-01590-0","DOIUrl":"https://doi.org/10.1038/s42255-026-01590-0","url":null,"abstract":"<p><p>K63-linked ubiquitination (K63) is closely associated with the interaction, intracellular trafficking or activity of tagged proteins. However, its role during metabolic dysfunction-associated steatohepatitis (MASH) is largely unknown. Here we show that UBE2N, a ubiquitin-conjugating enzyme that specializes in creating K63, is downregulated by THAP11 in human and mouse hepatocytes with MASH. While hepatocyte-specific Ube2n deficiency exacerbates western diet-induced MASH and fibrosis via PANoptosis and impaired mitophagy, its overexpression reverses these pathological phenotypes and restores hepatic homeostasis. Mechanistically, UBE2N increases PARKIN-mediated K63-p62 at lysine 420, promoting K63-p62 translocation into damaged mitochondria for mitophagic clearance. Ube2n deficiency, conversely, induces cytoplasmic p62 accumulation and NRF2 hyperactivation, driving PANoptosis. Additional Sqstm1 deletion mitigates Ube2n deletion-induced pathologies, highlighting the importance of p62 accumulation for MASH progression. Thus, our results demonstrate that hepatocyte UBE2N is essential for regulation of metabolic stress-mediated mitophagy and PANoptosis, and that p62 is a proof-of-concept target for treating MASH and fibrosis.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892007","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}
Nature metabolismPub Date : 2026-09-02DOI: 10.1038/s42255-026-01610-z
Jones K Ofori, Sabrina Ruhrmann, Axel Lindström, Alexander Perfilyev, Melina Martin, Alexandros Karagiannopoulos, Lucia Scisciola, Katja Kost, Josefine Jönsson, Åsa Nilsson, Boris Kantor, Monika Dudenhöffer-Pfeifer, Marianne G Rots, Anna Wendt, Tina Rönn, Lena Eliasson, Karl Bacos, Charlotte Ling
{"title":"Publisher Correction: Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.","authors":"Jones K Ofori, Sabrina Ruhrmann, Axel Lindström, Alexander Perfilyev, Melina Martin, Alexandros Karagiannopoulos, Lucia Scisciola, Katja Kost, Josefine Jönsson, Åsa Nilsson, Boris Kantor, Monika Dudenhöffer-Pfeifer, Marianne G Rots, Anna Wendt, Tina Rönn, Lena Eliasson, Karl Bacos, Charlotte Ling","doi":"10.1038/s42255-026-01610-z","DOIUrl":"https://doi.org/10.1038/s42255-026-01610-z","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881131","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":"Neutrophil serine proteases inhibit thermogenic capacity of visceral white adipose tissue.","authors":"Lufengzi Yuan, Xiaoping Wu, Jiuyu Zong, Mengxue Jiang, Sanxing Gao, Zixuan Zhang, Xiaowen Huang, Manyu Zhu, Minqi Xiang, Lin Wang, Zhihui Ping, Yong Pan, Dewei Ye, Aimin Xu, Ruby Lai Chong Hoo","doi":"10.1038/s42255-026-01598-6","DOIUrl":"https://doi.org/10.1038/s42255-026-01598-6","url":null,"abstract":"<p><p>Neutrophils and neutrophil-derived serine proteases (NSPs), including neutrophil elastase (NE) and proteinase 3 (PR3), are present in visceral fat of individuals and rodents with obesity, yet their roles in energy metabolism remain elusive. Here we show that neutrophil infiltration and NSP activation impair visceral fat browning in response to β-adrenergic receptor stimulation or cold exposure in male mice. Genetic deletion or local pharmacological inhibition of NE with sivelestat rescued visceral fat browning and enhanced thermogenesis. Mechanistically, NE/PR3 directly suppresses beige adipogenesis by arresting cell cycle via CDK4/cyclin D1 downregulation, impairs beige adipocyte differentiation by degrading insulin-like growth factor binding protein-3, and indirectly promotes M1 macrophage polarization. Administration of sivelestat suppressed diet-induced neutrophil infiltration, enhanced cold-induced visceral fat browning and decreased visceral fat content in mice. These findings reveal an unexpected inhibitory role of NSPs in visceral fat browning and suggest the potential of repurposing sivelestat as an anti-obese drug.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866029","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}
Nature metabolismPub Date : 2026-08-31DOI: 10.1038/s42255-026-01607-8
Avinash D Londhe, Niels B Danneskiold-Samsøe, Katrin J Svensson
{"title":"A brief guide to the identification and characterization of secreted molecules.","authors":"Avinash D Londhe, Niels B Danneskiold-Samsøe, Katrin J Svensson","doi":"10.1038/s42255-026-01607-8","DOIUrl":"https://doi.org/10.1038/s42255-026-01607-8","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866003","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}
Nature metabolismPub Date : 2026-08-31DOI: 10.1038/s42255-026-01606-9
Marcus J Tol, Rinke Stienstra
{"title":"Neutrophil proteases put the brakes on visceral beiging.","authors":"Marcus J Tol, Rinke Stienstra","doi":"10.1038/s42255-026-01606-9","DOIUrl":"https://doi.org/10.1038/s42255-026-01606-9","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865968","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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