Turning Off the Ferroptosis Switch: ACAA1-Driven PI3K/AKT/Nrf2 Signaling as a Novel Driver of Endometrial Cancer Progression.

Endometrial carcinoma (EC) is a prevalent gynecologic malignancy with rising global incidence. Dysregulated lipid metabolism promotes EC progression through estrogen synthesis, metabolic reprogramming, and tumor microenvironment remodeling. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, represents a potential therapeutic strategy, yet its resistance mechanisms in EC remain unclear. We identify Acetyl-CoA Acetyltransferase 1 (ACAA1), a key enzyme in mitochondrial fatty acid β-oxidation, as an oncogenic factor in EC. We demonstrate that ACAA1 is significantly upregulated in EC tissues via bioinformatic analysis and clinical samples. Functionally, ACAA1 overexpression enhances tumor cell proliferation, migration, energy metabolism, and lipid droplet synthesis in vitro, while accelerating tumor growth in vivo in xenograft models. Mechanistically, ACAA1 activates the PI3K/AKT pathway, leading to nuclear translocation of the transcription factor Nrf2. This ACAA1/PI3K/AKT/Nrf2 axis suppresses ferroptosis by regulating redox homeostasis and lipid peroxidation, thereby promoting EC progression. Our findings reveal ACAA1 as a novel regulator of ferroptosis resistance and tumorigenesis in EC, highlighting its potential as a promising therapeutic target for EC treatment.