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DNA damage-based radiotherapy plays a significant role in the treatment of TNBC. However, radioresistance continues to pose a significant challenge, often resulting in the unsuccessful outcome of radiation therapy for patients with TNBC. Type I gamma phosphatidylinositol phosphate kinase (PIPKI\u03b3), a key enzyme in phosphoinositide metabolism, is associated with poor prognostic outcomes in TNBC. Here, we discovered that PIPKI\u03b3 overexpression significantly boosts nonhomologous end joining (NHEJ), a principal mechanism for repairing DNA double-strand breaks (DSBs). This enhancement of NHEJ confers increased radioresistance in TNBC. At the molecular level, PIPKI\u03b3 directly interacts with LIG4, a crucial NHEJ component, and strengthens its interaction with XRCC4, a key regulator of LIG4 nuclear translocation. This facilitates LIG4\u2019s nuclear translocation, improving DNA repair efficiency and genomic stability in TNBC cells. Furthermore, elevated PIPKI\u03b3 levels enhance radioresistance in TNBC cells and tumors in xenograft models, whereas depleting PIPKI\u03b3 has the opposite effects. These insights reveal a new mechanism by which PIPKI\u03b3 promotes radioresistance through the facilitation of DSBs repair in TNBC. Collectively, our findings suggest that the PIPKI\u03b3-LIG4 interaction represents a potential therapeutic target for improving radiotherapy efficacy in TNBC patients.<\/jats:p>","DOI":"10.1038\/s41419-025-07894-5","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T13:09:25Z","timestamp":1753967365000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PIPKI\u03b3 promotes non-homologous end joining through LIG4 to enhance radiotherapy resistance in triple-negative breast cancer"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1740-6520","authenticated-orcid":false,"given":"Wenge","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9012-7554","authenticated-orcid":false,"given":"Haiping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7827-4402","authenticated-orcid":false,"given":"Zhigang","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2432-8011","authenticated-orcid":false,"given":"Ying","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"7894_CR1","doi-asserted-by":"publisher","first-page":"2750","DOI":"10.1172\/JCI45014","volume":"121","author":"BD Lehmann","year":"2011","unstructured":"Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. 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