PIAS3 promotes ferroptosis by regulating TXNIP via TGF-β signaling pathway in hepatocellular carcinoma

Wenfang Bao; Jialin Wang; Kailing Fan; Yong Gao; Jingde Chen

doi:10.1016/j.phrs.2023.106915

PIAS3 promotes ferroptosis by regulating TXNIP via TGF-β signaling pathway in hepatocellular carcinoma

Pharmacol Res. 2023 Oct:196:106915. doi: 10.1016/j.phrs.2023.106915. Epub 2023 Sep 9.

Authors

Wenfang Bao¹, Jialin Wang¹, Kailing Fan¹, Yong Gao², Jingde Chen³

Affiliations

¹ Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
² Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China. Electronic address: drgaoyong@tongji.edu.cn.
³ Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China; Department of Oncology, Ji'an Hospital, Shanghai East Hospital, Ji'an 343000, China. Electronic address: 1600092@tongji.edu.cn.

PMID: 37689128
DOI: 10.1016/j.phrs.2023.106915

Abstract

Ferroptosis has been suggested to play a potential role in cancer therapy as an iron-dependent programmed cell death mechanism distinct from other forms. Hepatocellular carcinoma (HCC) remains a great threat, with high mortality and limited therapeutic options. The induction of ferroptosis has emerged as a novel and promising therapeutic strategy for HCC. In the present study, we identified protein inhibitor of activated STAT3 (PIAS3) as a driver of ferroptosis in HCC using TMT-based quantitative proteomics and ferroptosis-related functional assays. Mechanistically, thioredoxin-interacting protein (TXNIP) was confirmed to be PIAS3 in promoting ferroptotic cell death, based on RNA-seq analysis. Knockdown of TXNIP degrades ferroptotic susceptibility caused by PIAS3-overexpression, whereas transfection-forced reexpression of TXNIP restores sensitivity to ferroptosis in PIAS3-downregulated cells. PIAS3 interacts with SMAD2/3 to activate transforming growth factor (TGF)-β signaling, leading to increased TXNIP expression. Our study revealed the critical role of PIAS3 in ferroptosis and a novel actionable axis-PIAS3/TGF-β/TXNIP that could govern ferroptotic sensitivity, paving the path for using ferroptosis as an efficient approach in HCC therapies.

Keywords: Ferroptosis; HCC; PIAS3; TGF-β signaling; TXNIP.