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Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan\u2010Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull\u2010down, immunofluorescence assays, acyl\u2010biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib\u2010induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc\u2010. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull\u2010down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de\u2010palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1300","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T05:55:05Z","timestamp":1687240505000},"source":"Crossref","is-referenced-by-count":107,"title":["Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de\u2010palmitoylation"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhehao","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Dermatology The First Affiliated Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Key Laboratory of 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