K48 and K63 linkage-competed ubiquitination of BECN1 promotes circPDE4D-mediated autophagy in chronic obstructive pulmonary diseaseDownload PDF Download PDF ArticleOpen accessPublished: 19 March 2026Ting-Ting Chen1,2 na1,Ming-Yu Wang1,2 na1,Jia-Ying Kang1,2 na1,Guo-Chun Ou1,2,Ru Wang1,2,Da-Wei Zhang1,2,Jing-Jing Ye1,2 &…Guang-He Fei ORCID: orcid.org/0000-0003-0064-20731,2 Cell Death & Disease , Article number: (2026) Cite this article We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.SubjectsMacroautophagyNon-coding RNAsRespiratory tract diseasesUbiquitylationAbstractChronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with limited clinical therapeutic effects to suspend its progression. Circular RNAs (circRNAs) possess regulatory effects in various diseases. However, circRNA-involved regulatory mechanisms in COPD are largely unknown. This study reveals the mechanism of SMURF1-mediated BECN1 ubiquitination, which is competed by Ub-K48 and Ub-K63, driving the circPDE4D-regulated autophagy. Here, circPDE4D is first identified as a downregulated circRNA in COPD. Among patients with COPD, the lower expression of circPDE4D is associated with the reduced lung function values of FEV1/FVC%, FEV1%, and MMEF75/25% predicted. Moreover, circPDE4D promotes autophagy and SG formation, as well as relieves inflammation in vitro and in vivo. Mechanistically, circPDE4D binds with miR545-3p to regulate SMURF1, which functions in apoptosis, autophagy, SG formation, and inflammation. Importantly, SMURF1 interacts with BECN1 to form a complex and recruits Ub-K63 to enhance K63-linked ubiquitination of BECN1, whereas it antagonizes Ub-K48 to govern BECN1 stability. In particular, circPDE4D is indispensable for the SMURF1-induced BECN1 ubiquitination and can enhance the stability of BECN1. Together, this circPDE4D-miR545-3p-SMURF1-BECN1 regulatory feedback loop underlies the circPDE4D-mediated functions and provides valuable insights into the therapeutic application potential of COPD drugs and biomarkers developed based on circPDE4D.Data availabilityData available on request from the authors. The uncropped western blotting imprints are uploaded as Supplementary Material.ReferencesLv X, Li K, Hu Z. Chronic obstructive pulmonary disease and autophagy. Adv Exp Med Biol. 2020;1207:559–67. https://doi.org/10.1007/978-981-15-4272-5_39.Google Scholar Labaki WW, Rosenberg SR. Chronic obstructive pulmonary disease. Ann Intern Med. 2020;173:Itc17–itc32. https://doi.org/10.7326/aitc202008040.Google Scholar Christenson SA, Smith BM, Bafadhel M, Putcha N. Chronic obstructive pulmonary disease. 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Autophagy. 2025. https://doi.org/10.1080/15548627.2025.2481126.Download referencesFundingThis work was supported by grants from the Anhui Province clinical medical research transformation project (No. 202304295107020038) and Anhui University excellent research and innovation team plan (No. 2023AH010082).Author informationAuthor notesThese authors contributed equally: Ting-Ting Chen, Ming-Yu Wang, Jia-Ying Kang.Authors and AffiliationsDepartment of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, ChinaTing-Ting Chen, Ming-Yu Wang, Jia-Ying Kang, Guo-Chun Ou, Ru Wang, Da-Wei Zhang, Jing-Jing Ye & Guang-He FeiKey Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, Anhui Province, ChinaTing-Ting Chen, Ming-Yu Wang, Jia-Ying Kang, Guo-Chun Ou, Ru Wang, Da-Wei Zhang, Jing-Jing Ye & Guang-He FeiAuthorsTing-Ting ChenView author publicationsSearch author on:PubMed Google ScholarMing-Yu WangView author publicationsSearch author on:PubMed Google ScholarJia-Ying KangView author publicationsSearch author on:PubMed Google ScholarGuo-Chun OuView author publicationsSearch author on:PubMed Google ScholarRu WangView author publicationsSearch author on:PubMed Google ScholarDa-Wei ZhangView author publicationsSearch author on:PubMed Google ScholarJing-Jing YeView author publicationsSearch author on:PubMed Google ScholarGuang-He FeiView author publicationsSearch author on:PubMed Google ScholarContributionsTing-Ting Chen, Ming-Yu Wang, and Jia-Ying Kang: Writing - original draft, Data curation, Validation, Investigation, Methodology, Formal analysis, Conceptualization. Guo-Chun Ou and Ru Wang: Methodology. Da-Wei Zhang and Jing-Jing Ye: Formal analysis. Guang-He Fei: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing - review & editing.Corresponding authorCorrespondence to Guang-He Fei.Ethics declarationsCompeting interestsThe authors declare no conflict of interest.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Professor Mauro Piacentini GASupplementary informationOriginal data of Western blot (download DOCX )Supplemental Material of Figures and Tables (download PDF )Rights and permissionsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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