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One distinguishing feature of UTUC is its enhanced resistance to reactive oxygen species (ROS)-induced lipid peroxidation, a phenomenon closely associated with adverse clinical outcomes. However, the molecular mechanisms underlying this resistance remain largely unexplored. In this study, we identify LncPEDS1-AS, an ultra-long (&gt;6900\u2009nt) antisense lncRNA, as a key regulator of ROS resistance in UTUC. Mechanistically, LncPEDS1-AS interacts with the splicing factor DDX23, forming a nuclear RNA-protein complex that facilitates the splicing and maturation of PEDS1 pre-mRNA. PEDS1 encodes plasmanylethanolamine desaturase, which plays a protective role against lipid peroxidation. Based on these findings, we developed an antisense oligonucleotide (ASO) therapy strategy targeting LncPEDS1-AS, which effectively suppressed tumour growth and enhanced tumour cells\u2019 ROS sensitivity both in vitro and in vivo. Moreover, our findings also highlight the distinctive molecular features and regulatory capacity of ultra-long antisense lncRNAs such as LncPEDS1-AS, which merit further comprehensive exploration in cancer biology.<\/jats:p>","DOI":"10.1038\/s41419-025-08293-6","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T12:37:41Z","timestamp":1765197461000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["LncPEDS1-AS promotes UTUC resistance to lipid peroxidation by regulating PEDS1 expression via DDX23"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8109-808X","authenticated-orcid":false,"given":"Guanru","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuke","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichen","family":"Di","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0448-7402","authenticated-orcid":false,"given":"Guoqing","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1389-916X","authenticated-orcid":false,"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9482-147X","authenticated-orcid":false,"given":"Keqiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"8293_CR1","doi-asserted-by":"publisher","first-page":"e4000","DOI":"10.1136\/bmj.e4000","volume":"344","author":"MR Gokmen","year":"2012","unstructured":"Gokmen MR, Lord GM. 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