LncPTEC mediated homocysteine accumulation elevates oxidative stress via UBQLN1-dependent MTHFD1 ubiquitination in DKDDownload PDF Download PDF ArticleOpen accessPublished: 07 July 2026Qijia Wang1,2 na1,Tianhui Wu2,3 na1,Peiling Li1,2 na1,He Zha4 na1,Keqian Wu2 na1,Handeng Liu5,Rui Peng6,Xuemei Peng7,Ziyue Lin2,Dan Lv ORCID: orcid.org/0000-0001-7724-47141,Xiaohui Liao ORCID: orcid.org/0000-0002-2329-04561,Yan Sun ORCID: orcid.org/0000-0003-2595-09611,2 &…Zheng Zhang ORCID: orcid.org/0000-0002-0062-517X1,2 Cell Death & Disease (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.SubjectsMolecular biologyNon-coding RNAsAbstractDiabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and chronic kidney disease. Oxidative stress, a key driver of renal fibrosis and a hallmark of DKD pathological changes, has been extensively studied for its role in DKD progression. However, its specific mechanisms remain unclear. Here, we show that homocysteine (Hcy) accumulation in proximal tubular epithelial cells (PTECs) is a significant contributor to mitochondrial oxidative stress in DKD. Through single-cell RNA sequencing (scRNA-seq) screening, we identify lncPTEC, a DKD-associated long non-coding RNA (lncRNA) from the PTEC cluster. Notably, we find that upregulated lncPTEC correlates with elevated albuminuria in DKD patients and exacerbates mitochondrial oxidative stress, epithelial-mesenchymal transition (EMT) and renal tubular fibrosis both in vitro and in vivo. Mechanistically, lncPTEC is transcriptionally upregulated by the transcription factor specificity protein 1 (SP1) under hyperglycemic conditions. Furthermore, lncPTEC directly interacts with the established key factor of Hcy metabolism, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), promoting its ubiquitination and degradation via the ubiquitination-related protein UBQLN1. This process leads to Hcy accumulation, mitochondrial oxidative stress, and subsequent DKD progression. Hence, our findings elucidate the role of the lncPTEC/MTHFD1 axis in Hcy-mediated mitochondrial oxidative stress, offering potential diagnostic biomarkers and therapeutic targets for DKD.AcknowledgementsThe authors thank the First People’s Hospital of Zunyi for providing human plasma.FundingThis study was supported by the National Natural Science Foundation of China (No.82270876), CQMU Program for Youth Innovation in Future Medicine (W0173), Science and Technology Research Program of Chongqing Municipal Education Commission (CSTB2022NSCQ-MSX0126), and Key Discipline Clinical Laboratory Diagnostics Project of Guizhou Provincial Health Commission (QWjh[2021]160).Author informationAuthor notesThese authors contributed equally: Qijia Wang, Tianhui Wu, Peiling Li, He Zha, Keqian Wu.Authors and AffiliationsDepartment of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaQijia Wang, Peiling Li, Dan Lv, Xiaohui Liao, Yan Sun & Zheng ZhangDepartment of Cell Biology and Genetics, Basic Medical College, Chongqing Medical University, Chongqing, ChinaQijia Wang, Tianhui Wu, Peiling Li, Keqian Wu, Ziyue Lin, Yan Sun & Zheng ZhangSchool of Public Health and Laboratory, Qilu Medical University, Zibo, Shandong, ChinaTianhui WuDepartment of Laboratory Medicine, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, Guizhou, ChinaHe ZhaLaboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, ChinaHandeng LiuDepartment of Bioinformatics, Chongqing Medical University, Chongqing, ChinaRui PengDepartment of Neurology, Chongqing General Hospital (The Chongqing General Hospital of Chongqing University), Chongqing, ChinaXuemei PengAuthorsQijia WangView author publicationsSearch author on:PubMed Google ScholarTianhui WuView author publicationsSearch author on:PubMed Google ScholarPeiling LiView author publicationsSearch author on:PubMed Google ScholarHe ZhaView author publicationsSearch author on:PubMed Google ScholarKeqian WuView author publicationsSearch author on:PubMed Google ScholarHandeng LiuView author publicationsSearch author on:PubMed Google ScholarRui PengView author publicationsSearch author on:PubMed Google ScholarXuemei PengView author publicationsSearch author on:PubMed Google ScholarZiyue LinView author publicationsSearch author on:PubMed Google ScholarDan LvView author publicationsSearch author on:PubMed Google ScholarXiaohui LiaoView author publicationsSearch author on:PubMed Google ScholarYan SunView author publicationsSearch author on:PubMed Google ScholarZheng ZhangView author publicationsSearch author on:PubMed Google ScholarCorresponding authorsCorrespondence to Xiaohui Liao, Yan Sun or Zheng Zhang.Ethics declarationsEthics approval and consent to participateAll experimental protocols were approved by the Ethics Committee of Chongqing Medical University. Informed consent from the patients has been obtained. The human studies were carried out in compliance with the Declaration of Helsinki and with the approval of the First People’s Hospital of Zunyi (No. 2022-120). Animal experiments were approved by the Ethics Committee of Chongqing Medical University (No. 2022135).Consent for publicationAll the authors agree with the publication of the manuscript.Competing interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by: Dr George CalinSupplementary informationSupplementary information (download DOCX )Original Western blots (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. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Reprints and permissionsAbout this articleDownload PDF