IRX1 suppresses cervical squamous cell carcinoma progression by downregulating ACLY expression to inhibit lipid synthesis.

IRX1 functions as a tumor suppressor in cervical cancer; however, its underlying mechanism remains unclear. In this study, we observed that IRX1 expression is frequently downregulated in cervical cancer cells owing to promoter hypermethylation. Functionally, IRX1 overexpression suppressed cell proliferation, migration, and invasion, whereas IRX1 knockdown enhanced these malignant phenotypes. Mechanistically, IRX1 directly bound to the ATP-citrate lyase (ACLY) promoter and recruited NME3, thereby forming a transcriptional repressive complex. This IRX1-NME3/ACLY axis inhibited de novo fatty acid synthesis, as reflected by reduced levels of acetyl-CoA, malonyl-CoA, triglycerides, cholesterol, and lipid droplets. Consistently, ACLY overexpression partially reversed the suppressive effects of IRX1 on lipid metabolism and tumor progression. Collectively, our findings reveal that IRX1 functions as a metabolic tumor suppressor by transcriptionally repressing ACLY-mediated lipogenesis.