Selective Cancer Cell Killing via a Fluorofoldamer‐Based Proton Channel That Triggers Ferroptosis

ABSTRACT We report a new class of aromatic foldamer‐based artificial proton channels incorporating fluorinated building blocks, which exhibit high proton transport efficiency and selectivity. The lead channel, 2 , shows outstanding proton transport activity (EC 50 = 13.1–14.7 nM) and high selectivity (H + /Cl − = 249.7; H + /Na + = 23.9; H + /K + = 45.0), forming transmembrane channels without compromising membrane integrity or facilitating the transport of competing ions. By exploiting the unique acidic tumor microenvironment, 2 mediates proton influx to acidify the intracellular environment of cancer cells, inducing cell death via ferroptosis. This is evidenced by the downregulation of AKR1B1 and GPX4, corresponding increases in reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and lipid remodeling. Accordingly, 2 exhibits potent cytotoxicity across multiple cancer cell lines (IC 50 < 10 µM) and significantly suppresses tumor growth in vivo without observable systemic toxicity. This work establishes the first artificial proton channel (APC) that induces ferroptosis via channel‐mediated intracellular acidification, offering a membrane‐targeted anticancer strategy with low propensity for drug resistance.