Abstract Ferroptosis is an iron-dependent form of regulated cell death with emerging significance in cancer. However, its full regulatory network, particularly epigenetic regulation, remains poorly understood. Here, we identify the histone acetyltransferase GCN5 as a critical novel mediator of ferroptosis. We demonstrate that the ferroptosis inducers Erastin and RSL3 trigger reactive oxygen species (ROS) production, lipid peroxidation, and labile iron accumulation in a GCN5-dependent manner. Genetic knockdown or pharmacological inhibition of GCN5 ameliorated Erastin/RSL3-induced mitochondrial dysfunction (including ROS, lipid peroxidation, and impaired dynamics), restored endoplasmic reticulum (ER) homeostasis, and normalized autophagic flux. Furthermore, Erastin/RSL3 upregulated several transcription factors in a GCN5-dependent manner. Notably, HDAC inhibitor-induced cell death was synergistically enhanced by Erastin or RSL3, suggesting a compelling combination therapy strategy.In conclusion, our work establishes GCN5 as a central regulator of ferroptosis, governing its execution through mitochondrial, autophagic, and nuclear pathways. These findings nominate GCN5 as a therapeutic target to sensitize cancers to ferroptosis. Citation Format: Ling-Chu Chang, Shih-Kai Chiang, Shuen-Ei Chen. Targeting the histone acetyltransferase GCN5 sensitizes cancer cells to ferroptosis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4668.
Chang et al. (Fri,) studied this question.