%0 Journal Article
%A Zhang, Zhongyan
%A Zhou, Qi
%A Li, Zhenchong
%A Huang, Fuxin
%A Mo, Ke
%A Shen, Cheng
%A Niu, Xing
%A Hou, Baohua
%A Zhang, Chuanzhao
%A Huang, Shanzhou
%T DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma.
%J Drug resistance updates
%V 81
%@ 1368-7646
%C Oxford
%I Elsevier
%M DKFZ-2025-00581
%P 101224
%D 2025
%Z #EA:B440#
%X 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.
%K DTX2 (Other)
%K Ferroptosis (Other)
%K HSD17B4 (Other)
%K Lenvatinib resistance (Other)
%K Peroxisomal β-oxidation (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40058099
%R 10.1016/j.drup.2025.101224
%U https://inrepo02.dkfz.de/record/299845