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Here, we reveal that malic enzyme 1 (ME1) functions as a previously unrecognized sensor of L-lactate through direct binding at arginine 155 (R155), thereby potentiating malignancy. Mechanistically, L-lactate binding promotes the nuclear translocation of ME1, a process involving reduced acetylation at lysine 362 (K362) and facilitated by nuclear import of karyopherin-\u03b1 4 (KPNA4). Nuclear accumulation of ME1 enhances metastatic potential, which is correlated with increased interaction with hepatoma-derived growth factor (HDGF) and acquisition of an epithelial\u2012mesenchymal transition (EMT)-related phenotype. Under nutrient-deficient conditions, L-lactate promotes the assembly of a ME1-lactate dehydrogenase B (LDHB) complex, which enhances oxidative phosphorylation (OXPHOS) and increases ATP production, suggesting a metabolic adaptive mechanism that supports tumor cell survival. Notably, the ME1\n                    <jats:sup>R155A<\/jats:sup>\n                    mutation, which disrupts L-lactate binding, abolishes the protumorigenic effect of the L-lactate-ME1 axis on tumor progression in vivo. In conclusion, our findings identify ME1 as a direct sensor of L-lactate and support a model in which lactate-mediated signaling and metabolic adaptation converge on ME1 to regulate tumor cell plasticity in a context-dependent manner under heterogeneous metabolic conditions. These insights advance our understanding of the spatiotemporal control of metabolic adaptation in cancer and reveal a potential therapeutic target.\n                  <\/jats:p>","DOI":"10.1038\/s41392-026-02839-6","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T07:44:09Z","timestamp":1789112649000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Malic enzyme 1 senses L-lactate to determine tumor heterogeneity"],"prefix":"10.1038","volume":"11","author":[{"given":"Si-Yi","family":"Cao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kewen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Lin","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Ming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aihong","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengjun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7026-7067","authenticated-orcid":false,"given":"Miao","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0798-4730","authenticated-orcid":false,"given":"Wenyu","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8547-8518","authenticated-orcid":false,"given":"Qun-Ying","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"2839_CR1","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.cmet.2019.08.013","volume":"30","author":"J Kim","year":"2019","unstructured":"Kim, J. & DeBerardinis, R. 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