Silencing NRF2 enhances arsenic trioxide-induced ferroptosis in hepatocellular carcinoma cells

• DOI: 10.1371/journal.pone.0322746
• Publication Date: 2025-05-22T17:29:56Z
• Authors: Mi Huang; Duanzhuo Li; Zhengzhen Xia; Shengjie Liao; Wenxia Si; Chao Yuan; Yanli Liao; Weibin Wu; Minshu Jiang; Xin Yu; Yi Quan
• Keywords: Arsenic Trioxide; Viability assay

Objective Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with high mortality rates partially due to limited therapeutic options and drug resistance. Arsenic trioxide (ATO), compound clinically proven for acute promyelocytic leukemia (APL), has garnered attention its emerging efficacy in solid tumors, including HCC. However, the molecular mechanisms driving ATO’s antitumor activity HCC remain incompletely understood. In this study, we aimed elucidate ferroptosis-dependent effects ATO on propose potential strategy. Methods The response cells was evaluated using cell viability, wound healing, colony formation, Transwell migration assays, cycle analysis. ATO-induced ferroptosis assessed by measuring lipid peroxidation (via C11-BODIPY staining), intracellular iron levels, malondialdehyde (MDA) production. Western blotting performed quantify protein levels NRF2, HO-1, SLC7A11, GPX4; immunofluorescence staining employed determine NRF2 subcellular localization. Results exhibited significant cytotoxicity inhibited progression cells. Treatment resulted notable increase ROS MDA which were subsequently reversed inhibitors Fer-1 DFO. Mechanistically, induced inhibiting GPX4. Furthermore, downstream targets, HO-1 upregulated during ferroptosis. knockdown enhanced death. Conclusions significantly promoted cells, cytotoxic ATO.