YTHDC1 Orchestrates Glucose and Glutamate Rewiring to Overcome Lethal Metabolic Stress in Triple-Negative Breast Cancer.

Developing effective therapies for triple-negative breast cancer (TNBC) requires the identification of key molecular regulators. Here, among the major m6A modulators, we find that only the reader YTHDC1 is specifically overexpressed in TNBC and correlates to unfavorable prognosis. Mechanistically, YTHDC1 orchestrates glucose and glutamine metabolism in an m6A-dependent manner to confer robust adaptability to lethal metabolic stress in TNBC cells. It not only stabilizes GLUT3 mRNA to sustain glucose uptake and NADPH production, but also reduces the mRNA stability of ATF4, thereby suppressing the overexpression of the cystine/glutamate antiporter SLC7A11 to prevent excessive cystine uptake and glutamate export. YTHDC1 knockdown simultaneously disrupts glucose metabolism and upregulates SLC7A11, triggering disulfidptosis in TNBC cells in vitro and in vivo. Leveraging this YTHDC1 knockdown-induced metabolic vulnerability, we develop an ATF4 mRNA-targeted nanotherapy, which delivers mRNA directly to the cytoplasm and bypasses m6A-mediated destabilization by YTHDC1 in the nucleus. By promoting SLC7A11 expression, therapeutic overexpression of ATF4 sensitizes TNBC cells to disulfidptosis upon GLUT inhibitor BAY-876 treatment, and to glutamate deprivation-induced cell death upon GLS inhibitor CB-839 treatment. Collectively, this work reveals YTHDC1 as a pivotal coordinator of the glucose-glutamine-cystine metabolic network and provides ATF4 mRNA nanomedicine-based combination strategies to improve TNBC therapeutic efficacy.