在正常氧气条件下的糖酵解，也被称为华尔堡效应，为许多肿瘤的生存和增殖提供了选择性优势。本研究调查了雌激素相关受体伽玛（ESRRG）在食管鳞状细胞癌（ESCC）代谢重编程中的作用。生物信息学分析表明，ESRRG的表达在ESCC组织中下调，并与不良临床结果相关。我们还检查了改变ESRRG表达对ESCC细胞增殖和代谢重编程的影响。我们探讨了ESRRG对ESCC中丙酮酸激酶M2（PKM2）表达和恶性行为的影响。我们的研究揭示了ESRRG对ESCC细胞生长、肿瘤发生和糖酵解活性的抑制作用，这是通过降调PKM2表达来介导的。我们进一步证明了ESRRG直接与PKM2启动子相互作用，抑制其在ESCC中的活性。值得注意的是，ESRRG特异性激动剂DY131通过调节糖酵解途径基因，在抑制ESCC细胞增殖和糖酵解活性方面具有卓越的活性。此外，我们验证了DY131作为免疫检查点抑制剂的增强活性，考虑到ESRRG-PKM2轴在乳酸调节ESCC细胞中的重要性。我们的研究结果为ESRRG-PKM2信号传导在调节ESCC细胞代谢和免疫检查点调节中的作用提供了新的见解。此外，我们认为DY131有望成为ESCC治疗的一种有前景的治疗药物。© 2023. BioMed Central Ltd.，Springer Nature的一部分。

Glycolysis under normoxic conditions, known as the Warburg effect, confers a selective advantage for the survival and proliferation of many tumors. In this study, we investigated the role of estrogen-related receptor gamma (ESRRG) in metabolic reprogramming in esophageal squamous cell carcinoma (ESCC).Bioinformatics analysis indicated that ESRRG expression was decreased in ESCC tissue and associated with poor clinical outcomes. We also examined the effects of altered ESRRG expression on the proliferation and metabolic reprogramming of ESCC cells. We explored the impact of ESRRG on Pyruvate kinase M2 (PKM2) expression and malignant behavior in ESCC.Our study revealed the inhibitory effects of ESRRG on the growth, tumorigenesis, and glycolysis activity of ESCC cells, which were mediated by the downregulation of PKM2 expression. We further demonstrated that ESRRG directly interacts with the PKM2 promoter to inhibit its activity in ESCC. Notably, the ESRRG-specific agonist, DY131, inhibited ESCC cell proliferation and glycolysis activity by modulating genes in the glycolysis pathway. Moreover, we verified that DY131 exhibits enhanced activity as an immune checkpoint inhibitor, considering the significance of the ESRRG-PKM2 axis in the lactate regulation of ESCC cells.Our findings provide novel insights into the role of ESRRG-PKM2 signaling in regulating ESCC cell metabolism and immune checkpoint regulation. Additionally, we suggest that DY131 holds promise as a promising therapeutic agent for ESCC treatment.© 2023. BioMed Central Ltd., part of Springer Nature.