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Mechanistically, DPP9 promotes UPS cell proliferation by inhibiting mitochondria-dependent ferroptosis. Specifically, DPP9 reduces intracellular reactive oxygen species (ROS) accumulation and confers resistance to ferroptosis. Conversely, DPP9 downregulation induces ferroptosis by enhancing ROS production and mitochondrial dysfunction. Moreover, N6-methyladenosine (m&lt;sup&gt;6&lt;\/sup&gt;A) methylation enhances DPP9 mRNA stability in UPS, contributing to its overexpression. DPP9 also activates the NRF2 signaling axis by suppressing KEAP1-mediated ubiquitination and subsequent degradation of NRF2. This stabilization of NRF2 underlies DPP9's ability to inhibit mitochondria-dependent ferroptosis. Collectively, our findings identify DPP9 as a critical regulator of ferroptosis resistance in UPS and suggest that targeting DPP9 may represent a promising therapeutic strategy-not only for UPS, but potentially for other malignancies driven by dysregulated ferroptosis.<\/p>","DOI":"10.1615\/critreveukaryotgeneexpr.2026063409","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T17:47:57Z","timestamp":1772214477000},"page":"27-47","source":"Crossref","is-referenced-by-count":0,"title":["DPP9 Expression in a PDTX Model of Undifferentiated Pleomorphic Sarcoma Reduced Mitochondrial Damage-Induced Ferroptosis for Diagnosis and Guidance for Individualized Clinical Treatment"],"prefix":"10.1615","volume":"36","author":[{"given":"Jing","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinjuan","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianting","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhou","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"613","reference":[{"key":"2","doi-asserted-by":"crossref","unstructured":"Bowes AL, Waise S, Lesluyes T, Butters T, English C, Yan H, Verfaillie A, Davies C, Chen J, Nye E, Stone R, Manji J, Flanagan AM, Demeulemeester J, Tarabichi M, Pillay N, Van Loo P. 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