URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers

Zhiwen Ding, Yufei Pan, Taiyu Shang, Tianyi Jiang, Yunkai Lin, Chun Yang, Shujie Pang, Xiaowen Cui, Yixiu Wang, Xiao fan Feng, Mengyou Xu, Mengmiao Pei, Yibin Chen, Xin Li, Jin Ding, Yexiong Tan, Hongyang Wang (), Liwei Dong () and Lu Wang ()
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Zhiwen Ding: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Yufei Pan: Naval Medical University
Taiyu Shang: Fudan University
Tianyi Jiang: Naval Medical University
Yunkai Lin: Naval Medical University
Chun Yang: Children’s Hospital of Soochow University
Shujie Pang: Naval Medical University
Xiaowen Cui: Naval Medical University
Yixiu Wang: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Xiao fan Feng: Naval Medical University
Mengyou Xu: Naval Medical University
Mengmiao Pei: Naval Medical University
Yibin Chen: Naval Medical University
Xin Li: Naval Medical University
Jin Ding: Naval Medical University
Yexiong Tan: Naval Medical University
Hongyang Wang: Naval Medical University
Liwei Dong: Naval Medical University
Lu Wang: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 (SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.

Date: 2023
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DOI: 10.1038/s41467-023-41852-z

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