α-KG conformationally stabilizes nuclear GLUD1-SNAIL complex to fuel trans-endothelial migration in metastasis

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Abstract Trans-endothelial migration (TEM) is a critical rate-limiting barrier in tumor metastasis, yet its mechanistic basis remains poorly defined. Here we show that α-ketoglutarate (α-KG) and its metabolic enzyme glutamate dehydrogenase 1 (GLUD1) constitute a pivotal regulatory axis governing this process. Mechanistically, GLUD1 translocates to the nucleus, where α-KG binds to its non-catalytic site (K147) to induce a conformational change that stabilizes the GLUD1-SNAIL interaction, promoting assembly of a nuclear ternary complex. Notably, this complex is preferentially enriched in tumors, and specific blockade of K147 disrupts this assembly and abrogates metastatic effects. Our findings reveal a non-canonical role for GLUD1 and α-KG in transcriptional regulation and propose a therapeutic paradigm that selectively interferes with metabolite-dependent complex formation rather than enzymatic activity, offering a precise strategy to target TEM-driven metastatic cells.

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