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This study demonstrated the role of the glycolytic enzyme alpha-enolase (ENO1) in glycolysis and stemness in gastric cancer (GC). High ENO1 expression was associated with poor prognosis and promoted malignant phenotypes and stem-like characteristics in patients with GC. Mechanistically, ENO1 directly stimulates lactate and ATP production by regulating glycolysis, affecting lactate homeostasis and intracellular ATP pools, and coregulating the AMPK\/mTOR and PI3K\/AKT signaling pathways. This ultimately drives GC stemness, epithelial\u2012mesenchymal transition (EMT)-related marker expression, self-renewal, migration, and invasion. Notably, the increase in the intracellular ATP pool can directly activate the PI3K\/AKT pathway in a concentration-dependent manner, thereby further stimulating glycolysis to form a positive feedback loop. The functional role of lactate depends on the simultaneous presence of glycolysis-derived ATP to synergistically activate the PI3K\/AKT pathway. Lactate homeostasis can also promote tumor stemness by increasing overall plactylation levels. Furthermore, pharmacological studies revealed that metformin combined with copanlisib significantly inhibited tumors by blocking the energy metabolism pathways PI3K\/AKT and AMPK\/mTOR. Our findings are the first to reveal the multifaceted role of ENO1 in mediating intracellular signaling and metabolic regulation to enhance stemness in GC. By establishing cell models with varying metabolite concentrations, we identified differential regulation of the PI3K\/AKT and AMPK\/mTOR pathways through lactate homeostasis and intracellular ATP pools, further confirming the metabolic crosstalk mechanism. Rationally, targeting multiple nodes along the ENO1-ATP\/lactate-AMPK\/PI3K\/AKT-mTOR axis may be effective for GC treatment, as indicated by the significant suppression of tumor growth by metformin (which inhibits ATP production) plus syrosingopine (which disrupts lactate homeostasis). In conclusion, the complex interplay between metabolism and tumor stemness offers novel therapeutic directions and potential treatment strategies for GC.<\/jats:p>","DOI":"10.1038\/s41392-025-02451-0","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:03:50Z","timestamp":1761869030000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Alpha-enolase influences ATP pool of cytoplasm and lactate homeostasis by regulating glycolysis in gastric cancer"],"prefix":"10.1038","volume":"10","author":[{"given":"Xiong","family":"Shu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiya","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaigai","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanting","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliang","family":"Ran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"2451_CR1","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s41571-023-00747-0","volume":"20","author":"AP Thrift","year":"2023","unstructured":"Thrift, A. 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