Bifunctional Ionophores for Cuproptosis Activation: Dual Targeting of Copper and Fe-S Protein Homeostasis.

Cellular resilience to therapy often arises from adaptive mechanisms that safeguard iron-sulfur (Fe-S) proteins. Here, we present a rational strategy to overcome such resilience by integrating two synergistic vulnerabilities, copper toxicity and Fe-S cluster homeostasis, into a single molecular scaffold. Inspired by a bacterial sulfur mobilization (SUF) inhibitor, we hybridized its core structure with a copper-transporting 8-hydroxyquinoline moiety to generate HDQ, HDQ-S, HDQ-Ph, and HDQ-Me. They coordinate copper via hydroxyquinoline and efficiently transport copper into cancer cells, with HDQ-Me achieving an efficacy comparable to that of the clinical copper ionophore elesclomol (ES). Strikingly, HDQ alone suppresses Fe-S proteins across multiple functions, including respiration, iron homeostasis, and DNA replication. HDQ-mediated copper loading triggers cuproptosis hallmarks, DNA damage, and ATP collapse, generating a synergistic lethality. This work establishes HDQs as bifunctional tools that cotarget copper and Fe-S protein homeostasis, validating a convergent therapeutic strategy against resilient cells.