• LPS promotes inflammation and suppresses cuproptosis in THP-1 macrophages by upregulating HKDC1 via TLR4 and the transcription factor YY1.
• HKDC1 knockdown inhibits glycolysis and induces cuproptosis, revealing a novel link between glucose metabolism and copper-dependent cell death.
• HKDC1 interacts with HSCB and FDX1 to increase intracellular copper levels, driving cuproptosis.
• In vivo, HKDC1 knockdown alleviates acute sepsis by activating cuproptosis, suggesting a potential therapeutic strategy for inflammatory diseases.