2. Academic Validation
  3. Targeting GPX4 to Induce Ferroptosis Overcomes Chemoresistance Mediated by the PAX8-AS1/GPX4 Axis in Intrahepatic Cholangiocarcinoma

Targeting GPX4 to Induce Ferroptosis Overcomes Chemoresistance Mediated by the PAX8-AS1/GPX4 Axis in Intrahepatic Cholangiocarcinoma

  • Adv Sci (Weinh). 2025 May 20:e01042. doi: 10.1002/advs.202501042.
Zhi-Wen Chen 1,  Ji-Jun Shan 1,  Mo Chen 1,  Zong Wu 1,  Yi-Ming Zhao 1,  Hong-Xu Zhu 1,  Xin Jin 1,  Yi-Xiu Wang 1,  Yi-Bin Wu 1,  Zhen Xiang 1,  Zhi-Wen Ding 1,  Zhen-Hai Lin 1,  Long-Rong Wang 1,  Lu Wang 1
Affiliations

Affiliation

  • 1 Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
PMID: 40391780 DOI: 10.1002/advs.202501042
Abstract

The standard regimen of gemcitabine combined with cisplatin offers limited clinical benefits in the treatment of advanced intrahepatic cholangiocarcinoma (ICC) due to intrinsic or acquired resistance. Currently, effective biomarkers to predict and improve chemotherapy resistance in ICC are lacking. Here, it is reported that a long non-coding RNA (lncRNA), PAX8-AS1, reduces the efficacy of standard chemotherapeutic drugs. Mechanistically, PAX8-AS1 activates NRF2 by binding to p62, thereby promoting GPX4 transcription, and stabilizes GPX4 mRNA through interaction with IGF2BP3. The PAX8-AS1/GPX4 axis inhibits Ferroptosis and promotes resistance to gemcitabine and cisplatin. In preclinical models, the combination of the GPX4 inhibitor JKE-1674 with gemcitabine and cisplatin exhibits superior antitumor efficacy. These findings suggest a promising therapeutic strategy to improve chemotherapy efficacy in advanced ICC.

Keywords

GPX4; PAX8‐AS1; chemoresistance; ferroptosis; intrahepatic cholangiocarcinoma.

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