HOXA2 exerts anti-renal fibrosis effects through reducing endoplasmic reticulum stress via the upregulation of SIRT1Download PDF Download PDF ArticleOpen accessPublished: 30 December 2025Xin Li1 na1,Tian-Kui Ma2 na1,Xiao-Xu Deng3 na1,Sang Hai1,Fang Ma1,Yun Zou1,Qi Yang1,Hui Lyu ORCID: orcid.org/0000-0003-2864-55914,Yu-Xi Li5 &…Hong Ding ORCID: orcid.org/0009-0006-9968-778X1 Communications Biology , Article number: (2025) 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.SubjectsChronic kidney diseaseDNA methylationAbstractRelieving renal fibrosis are promising therapeutic strategies for chronic kidney disease (CKD). Here we showed that decreased homeobox A2 (HOXA2) expression with excessive ER stress activation were observed in the renal tissues of UUO mice established on male C57BL/6 mice and TGF-β1-induced human proximal tubular epithelial cells (HK-2 cells). After transfected HOXA2 overexpression plasmids into HK-2 cells and administered adeno-associated virus (AAV) containing HOXA2 to UUO mice, the expression of ER stress markers such as ATF6, GRP78 and CHOP decreased, renal dysfunction and fibrosis were significantly attenuated. Mechanistically, HOXA2 binds to the SIRT1 promoter, enhancing SIRT1 transcription and deacetylase activity, which led to ATF6 deacetylation and downregulation. The protective effect of HOXA2 was confirmed against the ER stress agonist thapsigargin. Moreover, DNMT1-mediated promoter methylation was identified as a potential mechanism for HOXA2 suppression in fibrosis. 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The study was supported by the National Natural Science Foundation of China (82402721), Liaoning Province Postdoctoral Science Fund (3110211225) and Science and Technology Project of Liaoning Province (2025080736-JH3/101).Author informationAuthor notesThese authors contributed equally: Xin Li, Tian-Kui Ma, Xiao-Xu Deng.Authors and AffiliationsNephrology Department, the Fourth Hospital of China Medical University, Shenyang, ChinaXin Li, Sang Hai, Fang Ma, Yun Zou, Qi Yang & Hong DingBiological Therapy Department, the First Hospital of China Medical University, Shenyang, ChinaTian-Kui MaPathology Department, Shengjing Hospital of China Medical University, Shenyang, ChinaXiao-Xu DengNeurology Department, the Fourth Hospital of China Medical University, Shenyang, ChinaHui LyuAnesthesiology Department, the Fourth Hospital of China Medical University, Shenyang, ChinaYu-Xi LiAuthorsXin LiView author publicationsSearch author on:PubMed Google ScholarTian-Kui MaView author publicationsSearch author on:PubMed Google ScholarXiao-Xu DengView author publicationsSearch author on:PubMed Google ScholarSang HaiView author publicationsSearch author on:PubMed Google ScholarFang MaView author publicationsSearch author on:PubMed Google ScholarYun ZouView author publicationsSearch author on:PubMed Google ScholarQi YangView author publicationsSearch author on:PubMed Google ScholarHui LyuView author publicationsSearch author on:PubMed Google ScholarYu-Xi LiView author publicationsSearch author on:PubMed Google ScholarHong DingView author publicationsSearch author on:PubMed Google ScholarContributionsAll authors approved final version of manuscript. X.L., T.M., X.D., H.L., Y.L. and H.D. conceived and designed research and performed experiments. S.H., F.M., Y.Z., Q.Y. X.D. and X.L. analyzed data. X.L., T.M., H.L. and Y.L. prepared figures and edited text. X.L., T.M., and X.D. drafted manuscript. H.L., Y.L., and H.D. edited and revised manuscript. H.L., Y.L., and H.D. given final approval of the version to be published.Corresponding authorsCorrespondence to Hui Lyu, Yu-Xi Li or Hong Ding.Ethics declarationsCompeting interestsThe authors declare no competing interests.Peer reviewPeer review informationCommunications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editors: Dr Toshiro Moroishi and Dr Ophelia Bu. 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