Microenvironment-responsive ellagic acid-histidine-iron carbon-dot induces ferroptosis in HepG2 cells by disrupting iron and redox homeostasis

Hepatocellular carcinoma (HCC) represents a clinically challenging malignancy, for which existing therapeutic modalities still face substantial limitations. Ellagic acid, a naturally occurring polyphenol with anticancer potential against HCC, nevertheless suffers from notable intrinsic physicochemical drawbacks that restrict its direct therapeutic application. Here, we developed an ellagic acid-histidine-iron carbon-dot nanozyme (EA-His-Fe-CDs) through a one-pot hydrothermal route. EA-His-Fe-CDs formed dispersed sub-10-nm particles containing redox-active iron and remained colloidally stable in physiologically relevant media. The material exhibited acidity-enhanced iron release, glutathione (GSH) consumption, and hydroxyl-radical generation, establishing a microenvironment-responsive catalytic profile. In HepG2 cells, EA-His-Fe-CDs more effectively suppressed viability, DNA synthesis, and migration-associated wound closure than EA, EA-CDs, or EA-Fe-CDs. Increasing exposure elevated reactive oxygen species (ROS) and labile iron, depolarized mitochondrial membranes, depleted cellular antioxidant capacity, and promoted lipid peroxidation. These responses were accompanied by suppression of the SLC7A11/GSH/GPX4 defense axis, altered TFR1 and FTH1 expression, increased ACSL4 and ALOX15, and attenuation of Nrf2/HO-1 signaling. GSH replenishment and ferrostatin-1 rescued the cellular phenotype at distinct mechanistic levels, supporting a lipid-peroxidation-dependent ferroptotic mechanism associated with iron dysregulation rather than nonspecific oxidative injury. Collectively, EA-His-Fe-CDs integrate responsive iron mobilization with antioxidant disruption to induce ferroptosis in hepatocellular carcinoma cells.