The study identifies GAS41, a YEATS domain-containing protein, as a regulator of ferroptosis. Through genome-wide CRISPR-Cas9 screenings, GAS41 is found to be a repressor of ferroptosis by interacting with NRF2 and promoting its transcriptional activity on genes like SLC7A11 and GCLC. GAS41 recognizes the H3K27-acetylation marker and recruits NRF2 to the *SLC7A11* promoter, acting as an anchor for NRF2 on chromatin. This interaction is critical for the transcriptional activation of NRF2 targets. The loss of GAS41 increases cell sensitivity to ferroptosis and tumor suppression in vivo, suggesting that GAS41-mediated ferroptosis defense contributes to tumor growth. The study reveals a novel mechanism for GAS41-mediated regulation of transcription by anchoring NRF2 on chromatin, providing a model for the regulation of transcriptional factors by histone markers.The study identifies GAS41, a YEATS domain-containing protein, as a regulator of ferroptosis. Through genome-wide CRISPR-Cas9 screenings, GAS41 is found to be a repressor of ferroptosis by interacting with NRF2 and promoting its transcriptional activity on genes like SLC7A11 and GCLC. GAS41 recognizes the H3K27-acetylation marker and recruits NRF2 to the *SLC7A11* promoter, acting as an anchor for NRF2 on chromatin. This interaction is critical for the transcriptional activation of NRF2 targets. The loss of GAS41 increases cell sensitivity to ferroptosis and tumor suppression in vivo, suggesting that GAS41-mediated ferroptosis defense contributes to tumor growth. The study reveals a novel mechanism for GAS41-mediated regulation of transcription by anchoring NRF2 on chromatin, providing a model for the regulation of transcriptional factors by histone markers.