GAS41 is a YEATS domain-containing protein that acts as a histone reader and oncogene. This study identifies GAS41 as a repressor of ferroptosis by anchoring NRF2 on chromatin. Through genome-wide CRISPR-Cas9 screening, GAS41 was found to regulate ferroptosis by interacting with NRF2 and activating its targets, such as SLC7A11. GAS41 recognizes the H3K27-acetylation marker and recruits NRF2 to the SLC7A11 promoter, facilitating transcriptional activation. GAS41 also plays a critical role in oncogenesis by modulating ferroptosis. The study reveals that GAS41 anchors NRF2 on chromatin, enabling NRF2 to regulate antioxidant genes and modulate ferroptosis. This mechanism is essential for tumor growth and highlights the role of histone markers in regulating transcriptional factors. The findings suggest that targeting GAS41 could be a potential therapeutic strategy for cancers, as it modulates ferroptosis and tumor growth. The study also demonstrates that GAS41 interacts with NRF2 and other transcriptional factors, and its loss increases cellular vulnerability to ferroptosis. The results indicate that GAS41 is a key regulator of ferroptosis and tumor progression, and its interaction with NRF2 is crucial for its oncogenic function. The study provides insights into the molecular mechanisms underlying GAS41-mediated regulation of transcription and ferroptosis, offering a model for how transcriptional factors can be regulated by histone markers.GAS41 is a YEATS domain-containing protein that acts as a histone reader and oncogene. This study identifies GAS41 as a repressor of ferroptosis by anchoring NRF2 on chromatin. Through genome-wide CRISPR-Cas9 screening, GAS41 was found to regulate ferroptosis by interacting with NRF2 and activating its targets, such as SLC7A11. GAS41 recognizes the H3K27-acetylation marker and recruits NRF2 to the SLC7A11 promoter, facilitating transcriptional activation. GAS41 also plays a critical role in oncogenesis by modulating ferroptosis. The study reveals that GAS41 anchors NRF2 on chromatin, enabling NRF2 to regulate antioxidant genes and modulate ferroptosis. This mechanism is essential for tumor growth and highlights the role of histone markers in regulating transcriptional factors. The findings suggest that targeting GAS41 could be a potential therapeutic strategy for cancers, as it modulates ferroptosis and tumor growth. The study also demonstrates that GAS41 interacts with NRF2 and other transcriptional factors, and its loss increases cellular vulnerability to ferroptosis. The results indicate that GAS41 is a key regulator of ferroptosis and tumor progression, and its interaction with NRF2 is crucial for its oncogenic function. The study provides insights into the molecular mechanisms underlying GAS41-mediated regulation of transcription and ferroptosis, offering a model for how transcriptional factors can be regulated by histone markers.