Background: Endometrial cancer (EC) is one of the most common tumors in women. Estrogen-related receptor α (ERRα) has been reported to play a critical role in EC progression. However, the underlying mechanism of ERRα-mediated lipid reprogramming in EC remains elusive. Here, we show that transcription factor EB (TFEB)-ERRα axis promote lipid reprogramming to enhance invasion and metastasis of EC.Methods: TFEB and ERRα were analyzed and validated by RNA-sequencing data of EC tissues from the Cancer Genome Atlas (TCGA). TFEB-ERRα axis were assessed by dual-luciferase reporter and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The mechanism of TFEB-ERRα was investigated using loss-of-function and gain-of-function assays in vitro. Lipidomics and proteomics were performed to identify the ERRα-related lipid metabolism pathway. Furthermore, immunohistochemistry and lipidomics were performed in the tissues to verify the ERRα-related lipids.Results: Both TFEB and ERRα were highly expression in EC patients and related to EC progression. ERRα was the directly target of TFEB to mediate EC lipid metabolism. Lipidomics assays demonstrated that ERRα mainly effects on glycerophospholipids (GPs) and phosphatidylcholine (PC) and significantly elevates the ratio of PC/sphingomyelin (SM) in EC cells, which indicated the enhanced membrane fluidity. Specifically, ERRα induced unsaturated fatty acid (UFA)-containing PCs, phosphatidylglycerol (PGs), SMs etc. Combined proteomics analysis revealed the increase of UFA-containing GPs mainly related to mitochondrial function. Then, the levels of maximum oxygen consumption rates (OCRs), adenosine triphosphate (ATP) and lipid metabolism-related genes acc, fasn, acadm were found to be positively correlated with TFEB/ERRα expression. Mechanistically, our functional assays indicate that TFEB promoted EC cell migration in a ERRα-dependent manner by epithelial-mesenchymal transformation (EMT) signaling. Consistent with in vitro, higher PC(18:1/18:2)+HCOO were found in EC patients and those who with higher expression of TFEB/ERRα had a deeper myometrial invasion and lower serum high-density lipoprotein (HDL). Moreover, PC(18:1/18:2)+HCOO was an independent risk factor of the patients with lymph node metastasis and positively related to ERRα. Conclusion: Lipid reprogramming induced by TFEB-ERRα axis increases UFA- containing PC, PG and SM, which enhanced membrane fluidity via EMT signaling to promote EC progression. Of note, PC(18:1/18:2)+HCOO was the ERRα-associated potential predictor of EC metastasis.