Natural Polyphenol–Metal Supramolecular Nanocomplex for Ferroptosis Activation in Chemoresistant Hepatocellular Carcinoma

ABSTRACT Overcoming drug resistance remains a central challenge in cancer therapy, particularly in hepatocellular carcinoma (HCC), where elevated intracellular glutathione (GSH) levels suppress ferroptosis and limit therapeutic efficacy. Here, we report a natural polyphenol–metal supramolecular nanocomplex ( bm–Cur–NC ), assembled from bisdemethylcurcumin and Cu(II), with its successful formation and structural features confirmed by high‐resolution mass spectrometry (HR‐MS), 1 H NMR, UV–vis spectroscopy, scanning electron microscopy (SEM), atomic force microscopy (AFM), X‐ray photoelectron spectroscopy (XPS), and high‐resolution transmission electron microscopy (HR‐TEM). This nanocomplex simultaneously disrupts cytoplasmic and mitochondrial redox homeostasis to induce ferroptosis in cisplatin‐resistant HCC (HepG2/DDP) cells. The nanocomplex depletes GSH through a multifaceted “three‐stones‐for‐one‐bird” strategy: inhibiting GSH biosynthesis via downregulation of the system Xc − transporter component SLC7A11, and directly consuming GSH through Cu(II) redox cycling and Michael addition reactions. This coordinated GSH depletion resensitizes drug‐resistant HCC cells (HepG2/DDP) and triggers ferroptotic cell death in both the cytoplasm and mitochondria, accompanied by downregulation of key ferroptosis regulators, including glutathione peroxidase 4 (GPX4) and SLC7A11. Notably, bm–Cur–NC (10–20 µg mL −1 ) demonstrates potent antitumor efficacy in vivo with minimal systemic toxicity, while simultaneously suppressing ferroptosis‐ and resistance‐related proteins such as GPX4, SLC7A11, P‐glycoprotein (P‐gp), and glutathione S‐transferases (GSTs) in a nude mouse model. This study presents a supramolecular nanomaterial platform derived from biocompatible herbal components for redox‐based ferroptosis activation, offering a promising strategy to combat drug‐resistant cancers.