Urolithin A Restores Mitochondrial Function and Reverses Cardiac Remodeling in HFpEF

Urolithin A Restores Mitochondrial Function and Reverses Cardiac Remodeling in HFpEF | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Urolithin A Restores Mitochondrial Function and Reverses Cardiac Remodeling in HFpEF Chang-Myung Oh, Hangyul Song, Chahyun Yun, Yun Ju Choi, Wooju Jeong, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8585859/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure cases, yet no therapies are based on the underlying mechanisms. Mitochondrial dysfunction and defective mitophagy are key drivers of HFpEF pathogenesis. We investigated whether urolithin A (UA), a mitophagy activator produced by the gut microbiome, could reverse HFpEF. We used a two-hit mouse model involving a high-fat diet and L-NAME, administering UA during disease progression. Cardiac structure and function were evaluated using echocardiography, histology, and transmission electron microscopy. Mitochondrial bioenergetics were measured using Seahorse respirometry. Mitophagy flux was monitored via mt-Keima assays in H9c2 cells and hiPSC-derived cardiomyocytes. We also performed immunoblotting and integrated shotgun metagenomics, as well as lipidomics and single-nucleus RNA sequencing. UA was found to attenuate cardiac remodelling, fibrosis and diastolic dysfunction in HFpEF mice. Transmission electron microscopy revealed restored mitochondrial ultrastructure. Mitochondrial stress tests showed enhanced oxidative phosphorylation and glycolytic capacity. Immunoblotting confirmed the recovery of PINK1/Parkin-mediated mitophagy markers. Mt-Keima assays demonstrated increased mitophagic flux under HFpEF-like stress. Integrated multi-omics analysis revealed reduced ceramides and normalised mitochondrial quality control gene programmes. In conclusion, UA reversed cardiac remodelling in HFpEF by restoring mitophagy-mediated mitochondrial quality control, thus establishing its potential as mitochondria-targeted therapeutics. Health sciences/Diseases/Cardiovascular diseases/Heart failure Health sciences/Health care/Therapeutics Urolithin A Mitochondria Mitophagy HFpEF Full Text Additional Declarations There is no conflict of interest Supplementary Files SupplementaryTableEMM.xlsx SUPPLEMENTAL TABLE SupplementaryFigureEMM.pdf SUPPLEMENTARY FIGURE Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 11 Mar, 2026 Review # 2 received at journal 09 Mar, 2026 Reviewer # 2 agreed at journal 23 Feb, 2026 Review # 1 received at journal 23 Feb, 2026 Reviewer # 1 agreed at journal 03 Feb, 2026 Reviewers invited by journal 03 Feb, 2026 Submission checks completed at journal 14 Jan, 2026 First submitted to journal 13 Jan, 2026 Unknown event 13 Jan, 2026 Editor assigned by journal 12 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8585859","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":584803224,"identity":"514e3470-9bb5-4022-a93f-eb8e55ae492e","order_by":0,"name":"Chang-Myung 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