ArticlePublished: 31 May 2026Ting Yu ORCID: orcid.org/0009-0000-1927-34371,2,3 na1,Fan Yang ORCID: orcid.org/0000-0003-0010-17521 na1,Jijingru Yang ORCID: orcid.org/0009-0003-7663-05431 na1,Chang Shu1,Xitai Zhang1,Qin Liu1,Yajie Liu1,Xin Liang4,Min Li2,Wenjun Hu ORCID: orcid.org/0009-0000-9756-52085,Bilian Ke2,Xiaojun Zha ORCID: orcid.org/0000-0003-4006-07483 &…Ning Li ORCID: orcid.org/0000-0002-3326-928X1,2 Cell Death & Differentiation (2026) Cite this articleSubjectsEpigeneticsTranslational researchAbstractGlaucoma is a leading cause of irreversible blindness, and for patients unresponsive to medical therapy, glaucoma filtration surgery (GFS) is the primary intervention to lower intraocular pressure (IOP). However, postoperative scarring often leads to surgical failure. Here, we identify RNA demethylase ALKBH5 as a key regulator of fibrotic remodeling after GFS via an epitranscriptomic mechanism involving N6-methyladenosine (m6A) modification. In both human patients and rabbit models, increased vascular perfusion and decreased bleb height, measured by AS-OCTA and UBM, were associated with elevated IOP. Immunohistochemistry and single-cell RNA sequencing revealed upregulation of ALKBH5 in vascular endothelial cells (VECs) within scar tissue. In vitro, ALKBH5 knockdown in HUVECs impaired proliferation, migration, and capillary formation, while overexpression enhanced these processes. Co-culture experiments with human Tenon’s fibroblasts (HTFs) revealed that ALKBH5 promotes fibroblast migration and collagen expression. In vivo, rabbit GFS models and Alkbh5-deficient mice showed that ALKBH5 drives angiogenesis and collagen deposition, accelerating fibrosis. MeRIP-seq and RNA-seq identified NLRP3 as a downstream target of ALKBH5. ALKBH5 removes m6A modifications from NLRP3 mRNA, preventing YTHDF2-mediated degradation and stabilizing NLRP3 expression. These findings highlight the ALKBH5-YTHDF2-NLRP3 axis as a significant pathway in GFS-induced fibrosis, suggesting that targeting this epitranscriptomic mechanism in VECs may improve surgical outcomes.The alternative text for this image may have been generated using AI.This is a preview of subscription content, access via your institutionAccess optionsSubscribe to this journalReceive 12 print issues and online access269,00 € per yearonly 22,42 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutFig. 1: Angiogenesis and the upregulation of endothelial ALKBH5 expression are associated with filtering bleb scarring after GFS.The alternative text for this image may have been generated using AI.Fig. 2: Increased ALKBH5 expression is correlated with angiogenesis and collagen deposition in a postoperative rabbit model of GFS.The alternative text for this image may have been generated using AI.Fig. 3: ALKBH5 knockdown reduces scar formation by inhibiting angiogenesis and collagen deposition.The alternative text for this image may have been generated using AI.Fig. 4: Alkbh5 knockout mitigates bleb scar formation in mouse models of GFS.The alternative text for this image may have been generated using AI.Fig. 5: MeRIP-seq integrated with RNA-seq identifies NLRP3 as a potential ALKBH5-mediated target.The alternative text for this image may have been generated using AI.Fig. 6: ALKBH5 promotes the stability of NLRP3 mRNA through an m6A-YTHDF2-dependent mechanism.The alternative text for this image may have been generated using AI.Fig. 7: NLRP3 counteracts the role of ALKBH5 in promoting angiogenesis and collagen deposition.The alternative text for this image may have been generated using AI.Data availabilityThe values for all data points shown in the graphs, along with complete, uncropped blots and original gel images are provided in the Supplementary Materials. 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Additional support was provided by the Anhui Provincial Natural Science Foundation (Grant No. 2208085MH229), the Scientific Research Projects of Colleges and Universities in Anhui Province (Grant No. 2022AH051176), the Research Fund of Anhui Medical University (Grant No. 2021xkj136), the Youth Fund Cultivation Project of The First Affiliated Hospital of Anhui Medical University (Grant No. 2020kj12), the Research Project of Anhui Institute of Translational Medicine (2023zhyx-C31 and 2023zhyx-C44) and the Doctoral Research Fund of The First Affiliated Hospital of Anhui Medical University (Grant No. BSKY2019039). This study was also supported by horizontal research projects (Grant Nos. H2024034 and H2025058), funded through industry-university collaboration programs and hosted by Xiaojun Zha. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.Author informationAuthor notesThese authors contributed equally: Ting Yu, Fan Yang, Jijingru Yang.Authors and AffiliationsDepartment of Ophthalmology, The First Affiliated Hospital of Anhui Medical University, Hefei, ChinaTing Yu, Fan Yang, Jijingru Yang, Chang Shu, Xitai Zhang, Qin Liu, Yajie Liu & Ning LiDepartment of Ophthalmology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaTing Yu, Min Li, Bilian Ke & Ning LiDepartment of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, ChinaTing Yu & Xiaojun ZhaDepartment of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Eye Diseases, Shanghai, ChinaXin LiangDepartment of Blood Transfusion, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaWenjun HuAuthorsTing YuView author publicationsSearch author on:PubMed Google ScholarFan YangView author publicationsSearch author on:PubMed Google ScholarJijingru YangView author publicationsSearch author on:PubMed Google ScholarChang ShuView author publicationsSearch author on:PubMed Google ScholarXitai ZhangView author publicationsSearch author on:PubMed Google ScholarQin LiuView author publicationsSearch author on:PubMed Google ScholarYajie LiuView author publicationsSearch author on:PubMed Google ScholarXin LiangView author publicationsSearch author on:PubMed Google ScholarMin LiView author publicationsSearch author on:PubMed Google ScholarWenjun HuView author publicationsSearch author on:PubMed Google ScholarBilian KeView author publicationsSearch author on:PubMed Google ScholarXiaojun ZhaView author publicationsSearch author on:PubMed Google ScholarNing LiView author publicationsSearch author on:PubMed Google ScholarContributionsNL and XJZ conceived and supervised the project. NL, XJZ, and WJH designed the experiments. TY, FY, JJRY, CS, XTZ, QL, and YJL performed the experiments. TY, FY, and JJRY analyzed the data. TY, FY, JJRY, and CS drafted the manuscript. XL and ML visualized the data. XJZ, NL, BLK and WJH reviewed and revised the manuscript. All the authors read and approved the final version of the manuscript. The order of co-first authors was determined on the basis of the relative extent of their contributions to the study.Corresponding authorsCorrespondence to Wenjun Hu, Bilian Ke, Xiaojun Zha or Ning Li.Ethics declarationsCompeting interestsThe authors declare no competing interests.Ethics approvalThe use of human ocular tissues in this study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Anhui Medical University and was conducted in accordance with the Declaration of Helsinki (approval no. PJ 2024‑13‑43). Written informed consent was obtained from all participants or the legal representatives of the tissue donors prior to inclusion. All animal experiments complied with the Anhui Medical University Guidelines for the Care and Use of Laboratory Animals and were authorized by the Institutional Animal Care and Use Committee (DWLLPF-2025042901).Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplemental data (download DOCX )Uncropped blot and gel images (download DOCX )Source Data (download XLSX )Rights and permissionsSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsAbout this article