ArticlePublished: 26 July 2026Dandan Yin ORCID: orcid.org/0000-0002-2550-52541 na1,Chang Zhang ORCID: orcid.org/0009-0002-8896-44122 na1,Yuancheng Li3 na1,Jiali Dai4 na1,Tianyu Qu5 na1,Jun Su6,Xiyi Lu ORCID: orcid.org/0000-0003-2204-20524,Pingping Wu7,Liang Han ORCID: orcid.org/0000-0003-3578-29148 &…Erbao Zhang ORCID: orcid.org/0000-0002-5752-79769,10 Oncogene (2026) Cite this articleSave articleView saved researchSubjectsBiomarkersMolecular biologyNon-small-cell lung cancerAbstractRNA-binding proteins (RBPs) play crucial roles in tumorigenesis and cancer treatment. As metabolic reprogramming is known to participate in tumorigenesis, elucidation of the mechanisms of crosstalk between RBPs and metabolism could provide new insights into cancer biology. Here, we found that the RBP ZC3H18 is overexpressed in lung cancer through copy number gain, which exerts oncogenic functions. Mechanistically, ZC3H18 undergoes phase separation to transcriptionally activate a key metabolic enzyme, lactate dehydrogenase A (LDHA), by binding to the LDHA promoter, thus promoting glycolysis and the production of lactate. The accumulation of lactate, in turn, activates the transcription of ZC3H18 through histone H3K18 lactylation (H3K18la) and directly induces the lactylation of ZC3H18 at the Lys186 residue (K186) in post-translational, thus forming a positive ZC3H18/LDHA/lactate/ZC3H18 feedback loop. Moreover, the combination of ZC3H18 inhibition and an LDHA small-molecule inhibitor (GSK2837808A) exhibited better antitumor efficacy in lung cancer patient-derived xenograft (PDX) model, suggesting the therapeutic potential of targeting the ZC3H18/LDHA axis. Taken together, our findings clarify the dialogue between RBP phase separation and lactate metabolism from a novel perspective and suggest that the ZC3H18/LDHA axis may serve as a potential therapeutic target for lung cancer.This is a preview of subscription content, access via your institutionAccess optionsSubscribe to this journalReceive 50 print issues and online access269,00 € per yearonly 5,38 € 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: Screening and identification of genomic amplification activated ZC3H18 in NSCLC and its correlation with clinicopathological characteristics.Fig. 2: ZC3H18 promotes the proliferation and tumorigenicity of lung cancer.Fig. 3: ZC3H18 undergoes phase separation.Fig. 4: ZC3H18 promotes the tumorigenesis of lung cancer by affecting LDHA.Fig. 5: ZC3H18 directly transcriptionally activates LDHA by forming phase separation condensates.Fig. 6: The accumulation of lactate mediated by the ZC3H18/LDHA axis promotes the upregulation of ZC3H18 at the transcriptional level through histone H3K18 lactylation and induces the lactylation of ZC3H18 at the post-translational modification, thus forming a positive lactate feedback loop and facilitating tumorigenesis.Fig. 7: Lactate increases the phase separation capability of ZC3H18.Fig. 8: The therapeutic effect of ZC3H18/LDHA in lung cancer.Data availabilityThe data that support the findings of this study are available from the corresponding author upon reasonable request.ReferencesSiegel RL, Miller KD, Wagle NS, Jemal A. 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This work was also supported by the Talent Support Project of Nanjing Second Hospital [RCZD24003].Author informationAuthor notesThese authors contributed equally: Dandan Yin, Chang Zhang, Yuancheng Li, Jiali Dai, Tianyu Qu.Authors and AffiliationsClinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, ChinaDandan YinDepartment of Public Health, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaChang ZhangCentral Research Laboratory, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, ChinaYuancheng LiDepartment of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaJiali Dai & Xiyi LuDepartment of Respiratory Medicine, Zhongda Hospital of Southeast University, Nanjing, ChinaTianyu QuDepartment of Radiotherapy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, ChinaJun SuDepartment of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, ChinaPingping WuDepartment of Oncology, Xuzhou Central Hospital, Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, ChinaLiang HanDepartment of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, ChinaErbao ZhangJiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, ChinaErbao ZhangAuthorsDandan YinView author publicationsSearch author on:PubMed Google ScholarChang ZhangView author publicationsSearch author on:PubMed Google ScholarYuancheng LiView author publicationsSearch author on:PubMed Google ScholarJiali DaiView author publicationsSearch author on:PubMed Google ScholarTianyu QuView author publicationsSearch author on:PubMed Google ScholarJun SuView author publicationsSearch author on:PubMed Google ScholarXiyi LuView author publicationsSearch author on:PubMed Google ScholarPingping WuView author publicationsSearch author on:PubMed Google ScholarLiang HanView author publicationsSearch author on:PubMed Google ScholarErbao ZhangView author publicationsSearch author on:PubMed Google ScholarContributionsConception and design: EBZ. Development of methodology: CZ, DDY, TYQ and XYL. Acquisition of data: CZ, TYQ and JLD. Analysis of data: CZ, YCL, XYL and JS. Writing, review, and revision of manuscript: DDY and EBZ. Administrative, technical, or material support: LH, PPW and EBZ.Corresponding authorsCorrespondence to Chang Zhang, Xiyi Lu, Pingping Wu, Liang Han or Erbao Zhang.Ethics declarationsCompeting interestsThe authors declare no competing interests.Ethics approval and consent to participateThis study was approved by the Ethics Committee on Human Research of the First Affiliated Hospital of Nanjing Medical University and was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all the patients. 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