Thyroid Hormones Inhibit Tumor Progression and Enhance the Antitumor Activity of Lenvatinib in Hepatocellular Carcinoma Via Reprogramming Glucose Metabolism

Overview

Journal Cell Death Discov

Date 2025 Mar 7

PMID 40055330

Authors

Chun-Cheng Yang

Yu-Chuan Yan

Guo-Qiang Pan

Guang-Xiao Meng

Xiao Zhang

Lun-Jie Yan

Zi-Niu Ding

Dong-Xu Wang

Rui-Zhe Li

Guang-Zhen Li

Zhao-Ru Dong

Tao Li

Affiliations

Soon will be listed here.

Abstract

Thyroid hormones (THs) dysfunctions have been demonstrated to be associated with the risk of developing different types of cancers. The role of THs in regulating hepatocellular carcinoma (HCC) progression is still controversial. We demonstrated that T3 can inhibit HCC progression by enhancing the expression of THRSP. Mechanistically, T3 can activate tumor suppressor LKB1/AMPK/Raptor signaling as well as oncogenic PI3K/Akt signaling in HCC. Interestingly, T3-induced THRSP can augment the activation of LKB1/AMPK/Raptor signaling, yet inhibit T3-induced PI3K/Akt signaling activation, thereby preventing mTOR-induced nuclear translocation of HIF-1α, and ultimately suppressing ENO2-induced glycolysis and HCC progression. More importantly, the exogenous T3 enhances the antitumor effect of multikinase inhibitor lenvatinib in vitro and in vivo by regulating glycolysis. Our findings reveal the role and mechanism of THs in HCC progression and glucose metabolism and provide new potential therapeutic strategies for HCC treatment and drug resistance reversal.

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