The ATF4/PSAT1/JNK signaling axis suppresses ferroptosis to drive venetoclax resistance in AML.

Metabolic reprogramming has emerged as a key driver of therapy resistance in acute myeloid leukemia (AML). Here, we identify phosphoserine aminotransferase 1 (PSAT1) as a critical metabolic determinant of venetoclax (VEN) resistance through the suppression of ferroptosis. PSAT1 was consistently upregulated in VEN-resistant cell lines and relapsed patient samples. Mechanistically, the transcription factor ATF4 directly bound the PSAT1 promoter, enhancing its expression and subsequently promoting glutathione synthesis, depleting the labile iron pool, and attenuating lipid peroxidation. Concurrently, PSAT1 functioned to restrain JNK/c-Jun signaling. Knockdown of PSAT1 restored VEN sensitivity by triggering ferroptosis and modulating the expression of BCL-2 and GPX4. Clinically, elevated PSAT1 expression predicted poor patient survival. Our findings unveil the ATF4/PSAT1/JNK axis as a master regulator of ferroptosis in AML, revealing a druggable pathway to overcome VEN resistance.