TRIB3 knockdown increases the sensitivity of clear cell renal cell carcinoma to sunitinib by  inducing  ferroptosis

Zixuan  Chena,1,Xing  Jiaa,¹,Zhou  Wanga,¹,Yuesong  CaiC,An  Xu²,Chengtao  Hana, Sheng Chengb,* ,Min Liua,*

ABSTRACT

Sunitinib resistance presents a significant challenge in the treatment of clear cell renal cell carcinoma(ccRCC). The role of TRIB3,a newly identified oncogene,in tumor drug resistance has been widely studied.However,the mechanism by which TRIB3 contributes to sunitinib resistance in ccRCC has not been previously explored.This study aimed to investigate the mechanism through which TRIB3 regulates ferroptosis to increase the suscepti- bilityof ccRCC to sunitinib treatment.Bioinformatics analysis and experimental validation revealed that TRIB3 is significantly upregulated in ccRCC tissues and is associated with poor prognosis.Knockdown ofTRIB3 using siRNA transfection inhibited the proliferation and migration of ccRCC cells and induced ferroptosis.Following sunitinib treatment,TRIB3 knockdown increased cell sensitivity to sunitinib,enhanced the suppressive impact of sunitinib,and augmented sunitinib-induced ferroptosis.This study demonstrated that TRIB3 knockdown induces ferroptosis by targeting the SLC7A11/GPX4 pathway and enhances therapeutic efficacy of sunitinib for ccRCC, providing new insights and potential strategies to overcome the challenge of sunitinib resistance in ccRCC.

https://doi.org/10.1016/j.cellsig.2024.111421