Circular RNA circIGF1R controls cardiac fibroblast proliferation through regulation of carbohydrate metabolism
Abstract Excessive fibroblast proliferation and metabolic reprogramming are hallmarks of pathological cardiac remodeling, contributing significantly to impaired cardiac function. This study investigates the role of circular RNAs (circRNAs) in fibroblast metabolic reprogramming, an unexplored area wi...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-07167-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849472890952482816 |
|---|---|
| author | Arne Schmidt Kevin Schmidt Sonja Groß Dongchao Lu Ke Xiao Dimyana Neufeldt Sarah Cushman Nele Lehmann Sabrina Thum Angelika Pfanne Annette Just Andreas Pich Alexander Heinz Karsten Hiller Hannah Jill Hunkler Wilson Lek Wen Tan Roger Foo Christian Bär Thomas Thum Mira Jung |
| author_facet | Arne Schmidt Kevin Schmidt Sonja Groß Dongchao Lu Ke Xiao Dimyana Neufeldt Sarah Cushman Nele Lehmann Sabrina Thum Angelika Pfanne Annette Just Andreas Pich Alexander Heinz Karsten Hiller Hannah Jill Hunkler Wilson Lek Wen Tan Roger Foo Christian Bär Thomas Thum Mira Jung |
| author_sort | Arne Schmidt |
| collection | DOAJ |
| description | Abstract Excessive fibroblast proliferation and metabolic reprogramming are hallmarks of pathological cardiac remodeling, contributing significantly to impaired cardiac function. This study investigates the role of circular RNAs (circRNAs) in fibroblast metabolic reprogramming, an unexplored area with potential therapeutic implications. Through deep circRNA sequencing of cardiac tissue from heart failure (HF) patients and healthy individuals, we identified circIGF1R (hsa_circ_0005035), which exhibited dysregulation specifically in isolated cardiac fibroblasts derived from failing hearts. Silencing circIGF1R in patient-derived human cardiac fibroblasts (HCFs) led to accelerated proliferation, enhanced glycolytic activity, altered glucose trafficking, and increased glucose import. Conversely, administering recombinant circIGF1R inhibited the accelerated proliferation and enhanced glycolytic activity observed in HCFs from HF patients. Mechanistically, RNA pulldown assays and in silico analyses identified AZGP1 as a potential interaction partner facilitating the glycolysis-inhibitory and anti-proliferative functions of circIGF1R. Our findings identify circIGF1R as a pivotal regulator of fibroblast proliferation via metabolic reprogramming, particularly by glycolysis inhibition. Overexpression of circIGF1R demonstrated significant anti-fibrotic effects in cardiac fibroblasts derived from heart failure patients. These results underscore the therapeutic potential of circIGF1R in attenuating cardiac fibrosis by directly targeting fibroblast metabolism in the context of pathological cardiac remodeling. |
| format | Article |
| id | doaj-art-e1fa589b88c64e30882349eb16b37a9f |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-e1fa589b88c64e30882349eb16b37a9f2025-08-20T03:24:22ZengNature PortfolioScientific Reports2045-23222025-06-0115111710.1038/s41598-025-07167-3Circular RNA circIGF1R controls cardiac fibroblast proliferation through regulation of carbohydrate metabolismArne Schmidt0Kevin Schmidt1Sonja Groß2Dongchao Lu3Ke Xiao4Dimyana Neufeldt5Sarah Cushman6Nele Lehmann7Sabrina Thum8Angelika Pfanne9Annette Just10Andreas Pich11Alexander Heinz12Karsten Hiller13Hannah Jill Hunkler14Wilson Lek Wen Tan15Roger Foo16Christian Bär17Thomas Thum18Mira Jung19Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Toxicology, Hannover Medical SchoolDepartment of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität BraunschweigDepartment of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität BraunschweigInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Cell Biology, A*STARInstitute of Molecular and Cell Biology, A*STARInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolInstitute of Molecular and Translational Therapeutic Strategies, Hannover Medical SchoolAbstract Excessive fibroblast proliferation and metabolic reprogramming are hallmarks of pathological cardiac remodeling, contributing significantly to impaired cardiac function. This study investigates the role of circular RNAs (circRNAs) in fibroblast metabolic reprogramming, an unexplored area with potential therapeutic implications. Through deep circRNA sequencing of cardiac tissue from heart failure (HF) patients and healthy individuals, we identified circIGF1R (hsa_circ_0005035), which exhibited dysregulation specifically in isolated cardiac fibroblasts derived from failing hearts. Silencing circIGF1R in patient-derived human cardiac fibroblasts (HCFs) led to accelerated proliferation, enhanced glycolytic activity, altered glucose trafficking, and increased glucose import. Conversely, administering recombinant circIGF1R inhibited the accelerated proliferation and enhanced glycolytic activity observed in HCFs from HF patients. Mechanistically, RNA pulldown assays and in silico analyses identified AZGP1 as a potential interaction partner facilitating the glycolysis-inhibitory and anti-proliferative functions of circIGF1R. Our findings identify circIGF1R as a pivotal regulator of fibroblast proliferation via metabolic reprogramming, particularly by glycolysis inhibition. Overexpression of circIGF1R demonstrated significant anti-fibrotic effects in cardiac fibroblasts derived from heart failure patients. These results underscore the therapeutic potential of circIGF1R in attenuating cardiac fibrosis by directly targeting fibroblast metabolism in the context of pathological cardiac remodeling.https://doi.org/10.1038/s41598-025-07167-3Circular RNACardiac fibrosisCardiac fibroblastCardiac metabolismGlycolysisProliferation |
| spellingShingle | Arne Schmidt Kevin Schmidt Sonja Groß Dongchao Lu Ke Xiao Dimyana Neufeldt Sarah Cushman Nele Lehmann Sabrina Thum Angelika Pfanne Annette Just Andreas Pich Alexander Heinz Karsten Hiller Hannah Jill Hunkler Wilson Lek Wen Tan Roger Foo Christian Bär Thomas Thum Mira Jung Circular RNA circIGF1R controls cardiac fibroblast proliferation through regulation of carbohydrate metabolism Scientific Reports Circular RNA Cardiac fibrosis Cardiac fibroblast Cardiac metabolism Glycolysis Proliferation |
| title | Circular RNA circIGF1R controls cardiac fibroblast proliferation through regulation of carbohydrate metabolism |
| title_full | Circular RNA circIGF1R controls cardiac fibroblast proliferation through regulation of carbohydrate metabolism |
| title_fullStr | Circular RNA circIGF1R controls cardiac fibroblast proliferation through regulation of carbohydrate metabolism |
| title_full_unstemmed | Circular RNA circIGF1R controls cardiac fibroblast proliferation through regulation of carbohydrate metabolism |
| title_short | Circular RNA circIGF1R controls cardiac fibroblast proliferation through regulation of carbohydrate metabolism |
| title_sort | circular rna circigf1r controls cardiac fibroblast proliferation through regulation of carbohydrate metabolism |
| topic | Circular RNA Cardiac fibrosis Cardiac fibroblast Cardiac metabolism Glycolysis Proliferation |
| url | https://doi.org/10.1038/s41598-025-07167-3 |
| work_keys_str_mv | AT arneschmidt circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT kevinschmidt circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT sonjagroß circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT dongchaolu circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT kexiao circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT dimyananeufeldt circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT sarahcushman circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT nelelehmann circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT sabrinathum circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT angelikapfanne circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT annettejust circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT andreaspich circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT alexanderheinz circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT karstenhiller circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT hannahjillhunkler circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT wilsonlekwentan circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT rogerfoo circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT christianbar circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT thomasthum circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism AT mirajung circularrnacircigf1rcontrolscardiacfibroblastproliferationthroughregulationofcarbohydratemetabolism |