Hsp90αpromotes chemoresistance in pancreatic cancer by regulating Keap1-Nrf2 axis and inhibiting ferroptosis  

作　　者：Bin Liu Zhiyuan Chen Zhaoxing Li Xinya Zhao Weigang Zhang Ao Zhang Longxing Wen Xiaoming Wang Shuying Zhou Daohai Qian 

机构地区：[1]Department of Hepatobiliary Surgery,the First Affiliated Hospital of Wannan Medical College,Wuhu 240001,China [2]Pharmaceutical Research and Development Center,School of Pharmacy,Wannan Medical College,Wuhu 240001,China [3]School of Basic Medicine,Wannan Medical College,Wuhu 240001,China [4]Department of Nursing,Fudan University Shanghai Cancer Center,Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China

出　　处：《Acta Biochimica et Biophysica Sinica》2025年第2期295-309,共15页生物化学与生物物理学报(英文版)

基　　金：supported by the grants from the Anhui Province Educational Natural Science Project(No.2023AH040254);the Anhui Province Health Commission Key Project(No.AHWJ2023BAc10049);the Anhui Province Key Research and Development Project(No.202004j07020051);the Yijishan Hospital Talent Introduction and Peak Plans(Nos.YR202122,GF2019T03,and GF2019G03).

摘　　要：Chemoresistance is the primary reason for poor prognosis in patients with pancreatic cancer(PC).Recent studies have indicated that ferroptosis may improve chemoresistance,but the underlying mechanisms remain unclear.In this study,significant upregulation of heat shock protein 90α(Hsp90α)expression is detected in the peripheral blood and tissue samples of patients with chemoresistant PC.Further studies reveal that Hsp90αpromotes the proliferation,migration,and invasion of a chemoresistant pancreatic cell line(Panc-1-gem)by suppressing ferroptosis.Hsp90αcompetitively binds to Kelch-like ECH-associated protein 1(Keap1),liberating nuclear factor erythroid 2-related factor 2(Nrf2)from Keap1 sequestration.Nrf2 subsequently translocates into the nucleus and activates the glutathione peroxidase 4(GPX4)pathway,thereby suppressing ferroptosis.This process further worsens the chemoresistance of PC cells.This study provides valuable insight into potential molecular targets to overcome chemoresistance in PC.It sheds light on the intricate mechanisms linking Hsp90αand ferroptosis to chemoresistance in PC and provides a theoretical foundation for the development of novel therapeutic strategies.

关 键 词：heat shock protein 90α Keap1-Nrf2 axis ferroptosis pancreatic cancer chemoresistance 

分 类 号：R73[医药卫生—肿瘤]