Targeting Galectin-1 with Triptolide Induces Ferroptosis in Oral Squamous Cell Carcinoma

TL;DR

Triptolide, a natural compound, may help treat oral cancer by inducing a type of cell death called ferroptosis through targeting Galectin-1, a protein linked to poor outcomes in this disease.

Contribution

This study reveals that Triptolide induces ferroptosis in oral cancer by suppressing Galectin-1, offering a novel therapeutic strategy.

Findings

TPL reduces cell viability and increases lipid ROS in oral cancer cells.

TPL downregulates GPX4 and Galectin-1 in vitro and in tumor models.

High Galectin-1 expression correlates with worse survival in oral cancer patients.

Abstract

Oral squamous cell carcinoma (OSCC) remains a challenging malignancy, particularly in advanced stages where current treatments are often ineffective. In this study, we investigated the therapeutic potential of Triptolide (TPL), a natural compound, in OSCC. Our results show that TPL induces ferroptosis-associated cell death by increasing lipid peroxidation and suppressing Galectin-1, a protein frequently overexpressed in OSCC and associated with poor clinical outcomes. Evidence from cell-based experiments, animal models, and patient tissue analyses supports a role for TPL in inhibiting tumor growth and modulating ferroptosis-related markers. Collectively, these findings suggest that targeting Galectin-1 may enhance ferroptosis susceptibility and represent a potential therapeutic strategy for OSCC.

Background: Oral squamous cell carcinoma (OSCC) remains clinically challenging, particularly in advanced disease, where treatment resistance limits therapeutic outcomes. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential anticancer vulnerability. Galectin-1 (Gal-1/LGALS1), a β-galactoside–binding lectin frequently overexpressed in OSCC, is associated with tumor progression and unfavorable prognosis; however, its involvement in ferroptosis regulation remains incompletely understood. Methods: To investigate whether Triptolide (TPL) influences ferroptosis-associated responses through Gal-1 modulation, OSCC cell lines (SAS and HSC-3) were treated with TPL and analyzed for cell viability, lipid reactive oxygen species (ROS) accumulation, and glutathione peroxidase 4 (GPX4) expression. Publicly available The Cancer Genome Atlas (TCGA) datasets were examined to evaluate Gal-1 expression patterns and survival associations. An OSCC xenograft mouse model was further used to assess the antitumor effects of TPL and changes in ferroptosis-related markers in vivo. Results: TPL treatment reduced cell viability and increased lipid ROS accumulation in OSCC cells, accompanied by downregulation of GPX4 expression. Gal-1 expression was also decreased following TPL exposure in vitro and in xenograft tumors. Analysis of TCGA data revealed that elevated Gal-1 expression was significantly associated with poorer overall survival in OSCC patients. Conclusions: These findings indicate that TPL induces ferroptosis-associated responses in OSCC and suggest that this effect is partly mediated through modulation of Gal-1 expression. Gal-1 may represent a clinically relevant factor influencing ferroptosis susceptibility, and targeting this pathway warrants further investigation as a potential therapeutic strategy for OSCC.

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