铁死亡已被认为在癌症治疗中发挥潜在作用，作为与其他形式不同的铁依赖性程序性细胞死亡机制。肝细胞癌（HCC）仍然是一个巨大威胁，具有高死亡率和有限的治疗选择。诱导铁死亡已被证明是一种新颖且有前景的HCC治疗策略。在本研究中，我们利用TMT基于定量蛋白质组学和与铁死亡相关的功能实验，确定了激活STAT3的蛋白质抑制剂（PIAS3）在HCC中驱动铁死亡。从RNA序列分析得出，机械上，已确认硫氧还蛋白交互蛋白（TXNIP）是PIAS3在促进铁死亡中的推动因素。TXNIP的沉默降解了由PIAS3过表达引起的铁死亡敏感性，而强迫转染TXNIP的重新表达则恢复了PIAS3下调细胞对铁死亡的敏感性。PIAS3与SMAD2/3相互作用以激活转化生长因子（TGF）-β信号传导通路，导致TXNIP表达增加。我们的研究揭示了PIAS3在铁死亡中的关键作用，并揭示了一个新颖的可操作的PIAS3/TGF-β/TXNIP轴，可以控制铁死亡敏感性，为在HCC治疗中使用铁死亡作为高效方法铺平道路。版权所有 © 2023。由Elsevier Ltd.出版。

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.Copyright © 2023. Published by Elsevier Ltd.