# Fucoxanthin Induces Ferroptosis in Hypopharyngeal Carcinoma Cells by Activating the p53/SLC7A11/GPX4 Axis

## TL;DR

Fucoxanthin, a compound from brown algae, can trigger a specific type of cell death in hypopharyngeal cancer cells through a newly identified pathway involving p53, SLC7A11, and GPX4.

## Contribution

This study reveals a novel mechanism by which fucoxanthin induces ferroptosis in hypopharyngeal carcinoma via the p53/SLC7A11/GPX4 axis.

## Key findings

- Fucoxanthin increases intracellular Fe2+ and ROS levels, leading to lipid peroxide accumulation and ferroptosis in Fadu cells.
- Fucoxanthin reduces cysteine and GSH levels and disrupts mitochondrial membrane potential, effects reversed by ferroptosis inhibitors.
- Pharmacological inhibition of p53 attenuates fucoxanthin-induced cytotoxicity and ferroptosis, confirming the role of the p53/SLC7A11/GPX4 axis.

## Abstract

Fucoxanthin, a marine carotenoid abundantly derived from brown algae, has been increasingly recognized for its broad-spectrum antitumor activities; however, its role in regulating ferroptosis remains insufficiently defined. Hypopharyngeal carcinoma is a highly aggressive head and neck malignancy with limited therapeutic options, highlighting the need for novel marine-derived anticancer agents. In this study, we investigated whether fucoxanthin induces ferroptosis in human hypopharyngeal carcinoma cells (Fadu) and elucidated the underlying molecular mechanisms. Transcriptome profiling combined with in vitro validation revealed that fucoxanthin markedly upregulated heme oxygenase−1 (HO−1), leading to increased intracellular Fe2+ levels, excessive reactive oxygen species (ROS) generation, and pronounced lipid peroxide accumulation. Fucoxanthin simultaneously reduced cysteine and glutathione (GSH) levels, disrupted mitochondrial membrane potential, and triggered ferroptotic cell death, which was significantly reversed by the ferroptosis inhibitor ferrostatin−1. Mechanistically, fucoxanthin activated the p53 pathway while suppressing SLC7A11 and GPX4, thereby impairing antioxidant defenses. Pharmacological inhibition of p53 with Pifithrin−α markedly attenuated fucoxanthin-induced cytotoxicity and ferroptosis. Together, these findings identify fucoxanthin as a promising marine-derived compound capable of inducing ferroptosis via modulation of the p53/SLC7A11/GPX4 axis, providing new insights into its potential application in hypopharyngeal carcinoma therapy.