2. Academic Validation
  3. DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma

DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma

  • Drug Resist Updat. 2025 Jul:81:101224. doi: 10.1016/j.drup.2025.101224.
Zhongyan Zhang 1,  Qi Zhou 2,  Zhenchong Li 3,  Fuxin Huang 4,  Ke Mo 5,  Cheng Shen 5,  Xing Niu 6,  Baohua Hou 7,  Chuanzhao Zhang 8,  Shanzhou Huang 9
Affiliations

Affiliations

  • 1 Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China; South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China.
  • 2 Department of General Surgery, Hui Ya Hospital of the First Affiliated Hospital, Sun Yat-Sen University, Huizhou, Guangdong 516081, China; Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
  • 3 Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • 4 South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China.
  • 5 Experimental Center of ECBio, YuanDong International Academy Of Life Sciences, Hong Kong 999077, China.
  • 6 Experimental Center of ECBio, YuanDong International Academy Of Life Sciences, Hong Kong 999077, China. Electronic address: [email protected].
  • 7 Department of General Surgery, Heyuan Key Laboratory of Molecular Diagnosis & Disease Prevention and Treatment, Heyuan People's Hospital, Heyuan, Guangdong 517000, China; Maoming People's Hospital, Maoming, Guangdong 525000, China. Electronic address: [email protected].
  • 8 Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China; South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China. Electronic address: [email protected].
  • 9 Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China; South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China. Electronic address: [email protected].
PMID: 40058099 DOI: 10.1016/j.drup.2025.101224
Abstract

Aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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; Ferroptosis; HSD17B4; Lenvatinib resistance; Peroxisomal β-oxidation.

Figures
Products
Inhibitors & Agonists