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PIAS3/TGF-β/TXNIP axis promotes ferroptosis in HCC

ABSTRACT: Ferroptosis has been suggested to have a potential role in cancer therapy as an iron-dependent programmed cell death distinguished from other forms. Hepatocellular carcinoma (HCC) remains a great threat with high lethality and limited therapies. Induction of ferroptosis has emerged as a novel and promising therapeutic strategy for HCC. Here, we identify PIAS3 as a driver of ferroptosis in HCC through TMT-based quantitative proteomics and ferroptosis-related functional assays. Mechanistically, TXNIP is confirmed as a downstream of PIAS3 in promoting ferroptotic cell death based on RNA-seq analysis. The knockdown of TXNIP degrades ferroptotic susceptibility caused by PIAS3-overexpression, whereas the transfection-forced re-expression of TXNIP restores sensitivity to ferroptosis in PIAS3-downregulated cells. In the meantime, PIAS3 interacts with SMAD2/3 to activate TGF-β signaling, which leads to increased TXNIP expression. Our study uncovers 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 targeting ferroptosis as an efficient approach in HCC therapies.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jingde Chen

PROVIDER: PXD043038 | iProX | Thu Jun 15 00:00:00 BST 2023

REPOSITORIES: iProX

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