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), ¹H 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.

Keywords

drug resistance / ferroptosis / GSH / hepatocellular carcinoma (HCC) / mitochondria

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