Inspired by a bacterial SUF-system inhibitor, we integrated its core scaffold with copper-transporting 8-hydroxyquinoline moiety, yielding four derivatives (HDQ, HDQ-S, HDQ-Ph, and HDQ-Me). Functionally, HDQ-mediated copper loading triggers hallmark cuproptosis features, induces DNA damage, disrupts Fe-S proteins,and collapses ATP production, creating synergistic lethality.