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@ARTICLE{Zhang:299845,
      author       = {Z. Zhang and Q. Zhou and Z. Li$^*$ and F. Huang and K. Mo
                      and C. Shen and X. Niu and B. Hou and C. Zhang and S. Huang},
      title        = {{DTX}2 attenuates {L}envatinib-induced ferroptosis by
                      suppressing docosahexaenoic acid biosynthesis through
                      {HSD}17{B}4-dependent peroxisomal β-oxidation in
                      hepatocellular carcinoma.},
      journal      = {Drug resistance updates},
      volume       = {81},
      issn         = {1368-7646},
      address      = {Oxford},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-00581},
      pages        = {101224},
      year         = {2025},
      note         = {#EA:B440#},
      abstract     = {Emerging resistance to Lenvatinib, which is used as a
                      first-line agent for the treatment of advanced
                      hepatocellular carcinoma (HCC), is still a concern. The aim
                      of this study was to determine core factors of Lenvatinib
                      resistance (LR) and their underlying molecular
                      mechanisms.CRISPR screening in HCC cells was conducted,
                      which identified E3 ubiquitin ligase deltex 2 (DTX2) as a
                      core LR-related gene. In vivo and in vitro models were used
                      to clarify the function of DTX2 on LR and ferroptosis. The
                      upstream regulators and downstream effectors of DTX2 were
                      identified, revealing its complex regulatory network.DTX2
                      promoted anti-ferroptosis in LR HCC cells via downregulating
                      the peroxisomal β-oxidation enzyme HSD17B4. DTX2 induced
                      the ubiquitination-mediated degradation of HSD17B4,
                      resulting in lipid metabolism changes that were associated
                      mainly with docosahexaenoic acid (DHA)-containing PUFAs.
                      Notably, DHA supplements could reverse DTX2-induced
                      anti-ferroptosis and LR. Mechanistically, we uncovered that
                      DTX2 ubiquitinated the HSD17B4 SCP structural domain through
                      its RING structural domain and ubiquitinated the K645 site.
                      The upregulation of DTX2 expression was mediated by
                      JAK2-STAT3 pathway activation. The aberrant activation of
                      STAT3 in acquired LR promoted DTX2 transcription and
                      negatively regulated peroxisomal β-oxidation via
                      K48-ubiquitinated HSD17B4 and decreased DHA-phospholipids
                      levels, leading to the suppression of Lenvatinib-induced
                      ferroptosis in HCC.Our findings suggest that DTX2 attenuates
                      Lenvatinib-induced ferroptosis by inhibiting DHA
                      biosynthesis through HSD17B4-dependent peroxisomal
                      β-oxidation in HCC. The combination of DHA with Lenvatinib
                      could be a promising therapeutic strategy for patients with
                      LR HCC.},
      keywords     = {DTX2 (Other) / Ferroptosis (Other) / HSD17B4 (Other) /
                      Lenvatinib resistance (Other) / Peroxisomal β-oxidation
                      (Other)},
      cin          = {B440},
      ddc          = {610},
      cid          = {I:(DE-He78)B440-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40058099},
      doi          = {10.1016/j.drup.2025.101224},
      url          = {https://inrepo02.dkfz.de/record/299845},
}