Activation of SIRT3/AMPK/mTOR-mediated autophagy promotes quercetin-induced ferroptosis in oral squamous cell carcinoma

Тип публикации: Journal Article
Дата публикации: 2025-02-26
SAGE
scimago Q2
wos Q2
БС3
SJR: 0.726
CiteScore: 6.7
Impact factor: 3.2
ISSN: 09603271, 14770903
Краткое описание
Introduction

Quercetin has been reported to inhibit the growth of oral squamous cell carcinoma (OSCC), but the mechanism remains unclear. Therefore, our study aimed to investigate the involvement of sirtuin 3 (SIRT3) and the autophagy-dependent form of cell death, ferroptosis, in the pathogenesis of OSCC, and observe the impacts of quercetin on ferroptosis and SIRT3/AMPK/mTOR-mediated autophagy.

Methods

SIRT3 knock out or overexpressing SCC15 cell line was generated, treated with indicated drugs, and malondialdehyde (MDA) and ROS levels were measured. Roles of SIRT3 in regulating autophagy-mediated ferroptosis were assessed by immunoprecipitation and Western blotting.

Results

SIRT3 overexpression increased levels of MDA and ROS, reducing cell viability, and SIRT3 knockout produced the opposing effect. SIRT3 overexpression upregulated ATG16L1 expression and the conversion of LC3-Ⅰ to LC3-Ⅱ, triggering autophagy. Suppression of autophagy by ATG16L1 knockout impaired SIRT3-triggered ferroptosis. Use of an AMPK inhibitor antagonized the induction of ferroptosis by SIRT3 in SCC15 cells, indicating the involvement of the AMPK/mTOR pathway. Additionally, quercetin significantly increased the levels of SIRT3, p-AMPK, ATG16L1, and the ratio of LC3-Ⅱ/Ⅰ, but reduced cell viability and p-mTOR in SCC15 cells. Autophagy and AMPK inhibitors, or SIRT3 deletion significantly antagonized the impacts of quercetin on the autophagy-mediated ferroptosis in cancer cells.

Discussion

SIRT3 overexpression activated the AMPK/mTOR pathway and triggered ATG16L1-mediated autophagy, promoting ferroptosis in SCC15 cells, and we proposed that quercetin may be a promising therapeutic drug for OSCC.

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Wang J. et al. Activation of SIRT3/AMPK/mTOR-mediated autophagy promotes quercetin-induced ferroptosis in oral squamous cell carcinoma // Human and Experimental Toxicology. 2025. Vol. 44.
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Wang J., Yang J., Xiong D., Chen L. Activation of SIRT3/AMPK/mTOR-mediated autophagy promotes quercetin-induced ferroptosis in oral squamous cell carcinoma // Human and Experimental Toxicology. 2025. Vol. 44.
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TY - JOUR
DO - 10.1177/09603271251323753
UR - https://journals.sagepub.com/doi/10.1177/09603271251323753
TI - Activation of SIRT3/AMPK/mTOR-mediated autophagy promotes quercetin-induced ferroptosis in oral squamous cell carcinoma
T2 - Human and Experimental Toxicology
AU - Wang, Jin
AU - Yang, Jia-Hui
AU - Xiong, Di
AU - Chen, Ling
PY - 2025
DA - 2025/02/26
PB - SAGE
VL - 44
SN - 0960-3271
SN - 1477-0903
ER -
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@article{2025_Wang,
author = {Jin Wang and Jia-Hui Yang and Di Xiong and Ling Chen},
title = {Activation of SIRT3/AMPK/mTOR-mediated autophagy promotes quercetin-induced ferroptosis in oral squamous cell carcinoma},
journal = {Human and Experimental Toxicology},
year = {2025},
volume = {44},
publisher = {SAGE},
month = {feb},
url = {https://journals.sagepub.com/doi/10.1177/09603271251323753},
doi = {10.1177/09603271251323753}
}