IRX1 suppresses breast cancer progression by inhibiting fatty acid de novo synthesis through downregulating ACACA expression

Abstract Breast cancer remains a major threat to women’s health and survival worldwide. Iroquois homeobox 1 ( IRX1 ), a developmentally regulated transcription factor, acts as a tumor suppressor in several cancers. However, its mechanistic role in breast cancer remains elusive. In this study, we demonstrate that IRX1 is downregulated in breast cancer tissues and cell lines due to promoter hypermethylation. IRX1 functioned as a tumor suppressor both in vitro and in vivo. Mechanistically, IRX1 interacts with NME1 and promotes its nuclear localization. Subsequently, NME1 facilitates the transcriptional regulation of ACACA by IRX1 . The IRX1 - NME1 axis modulates de novo fatty acid synthesis and breast cancer progression by targeting ACACA . In conclusion, our findings reveal that the IRX1- NME1 / ACACA axis plays a critical role in de novo fatty acid synthesis and breast cancer progression, providing new insights into gene regulatory interactions and highlighting its potential as a novel therapeutic target for breast cancer.