GOT1 promotes endometrial cancer progression by regulating ferroptosis through the STAT3-GPX4 axis and attenuating medroxyprogesterone acetate sensitivity.

Ferroptosis plays a critical role in tumor development and treatment response, but its regulatory mechanisms in endometrial cancer (EC) are not well understood. This study aimed to identify ferroptosis-related genes in EC and explore their roles and mechanisms. Differentially expressed genes from EC datasets were intersected with ferroptosis-related gene sets to identify key candidates. The functional role of GOT1 was studied using in vitro assays, while transcriptomic and proteomic profiling were integrated to explore downstream pathways. Immunohistochemistry (IHC) was performed on 35 EC samples and 11 adjacent normal tissues. GOT1's contribution to medroxyprogesterone acetate (MPA) resistance was evaluated both in vitro and in vivo. GOT1 expression was significantly elevated in EC tissues and correlated with poor prognosis. Silencing GOT1 impaired EC cell proliferation and migration, increasing intracellular Fe²⁺, lipid ROS, and 4-HNE levels. IHC confirmed elevated GOT1, STAT3, GPX4, TFRC, TFAP4, and PAX8 in EC tissues. Transcriptome data showed that GOT1 knockdown reduced GPX4 and altered metabolism pathways. Overexpression of GPX4 reversed the ferroptosis and growth inhibition caused by GOT1 depletion. Proteomic analysis revealed that GOT1 physically interacts with STAT3 and functionally enhances STAT3-dependent transcription, thereby indirectly promoting GPX4 expression. GOT1 overexpression reduced EC cell sensitivity to MPA in vitro and in vivo, whereas GOT1 inhibition partially restored MPA responsiveness. It contributes to EC progression and ferroptosis resistance via the STAT3-GPX4 axis, diminishing MPA efficacy. GOT1 may serve as potential biomarker and therapeutic target to enhance ferroptosis-based strategies in EC.