Dihydroquercetin Activates AMPK/SIRT1/PGC-1α Signaling to Attenuate Arsenic Trioxide-Induced Apoptosis and Ferroptosis in AC16 Cells and HUVECs
- 1Department of Pharmacy, First Affiliated Hospital of Harbin Medical University, 23 YouZheng Str, Nangang District, Harbin 150007, China
Abstract
Arsenic trioxide (ATO) is a first-line therapeutic agent for acute promyelocytic leukemia (APL), but its clinical utility is constrained by dose-dependent cardiotoxicity. This study aimed to systematically evaluate the cytoprotective potential of dihydroquercetin (DHQ), a natural flavonoid derived from coniferous species with multimodal antioxidant properties, against ATO-induced cellular injury. An integrated combining network pharmacology with experimental validation was employed to elucidate the underlying molecular mechanisms. Cardiotoxicity models were established using AC16 human cardiomyocytes and human umbilical vein endothelial cells (HUVECs). Cytotoxicity, reactive oxygen species (ROS), mitochondrial membrane potential, DNA damage (γ-H2AX), apoptosis (TUNEL, Bcl-2, Bax, Caspase-3), and ferroptosis markers (GPX4, xCT, intracellular iron) were assessed. The AMPK/SIRT1/PGC-1α axis was validated using Compound C. ATO exposure induced significant cytotoxicity, oxidative stress, mitochondrial dysfunction, and activated both apoptosis and ferroptosis pathways. Co-treatment with DHQ dose-dependently attenuated these injuries. Mechanistically, DHQ activated AMPK/SIRT1/PGC-1α, increasing phosphorylated AMPK, SIRT1, and PGC-1α. Compound C abrogated DHQ-mediated pathway activation and its protection against oxidative stress, apoptosis, and ferroptosis. DHQ protects against ATO cardiotoxicity by activating the AMPK/SIRT1/PGC-1α pathway, thereby reducing oxidative stress and concurrently inhibiting apoptosis and ferroptosis. These findings position DHQ as a promising candidate for protecting cardiomyocytes and endothelial cells from ATO-induced injury.
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BibTeX
@article{zhang2026dihydroquercetin,
title = {{Dihydroquercetin Activates AMPK/SIRT1/PGC-1α Signaling to Attenuate Arsenic Trioxide-Induced Apoptosis and Ferroptosis in AC16 Cells and HUVECs}},
author = {Wenlei Zhang and Rui Duan and Xinsheng Duan and Sijing Tao and Haoxuan Li and Jinyan Li and Xinru Wang and Lijuan Yue and Kai Ren and Tianyu Zhao and Meihua Guo and Xiaoxiang Guan and Xin Hai},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198753},
url = {https://www.mdpi.com/1422-0067/27/19/8753},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Dihydroquercetin Activates AMPK/SIRT1/PGC-1α Signaling to Attenuate Arsenic Trioxide-Induced Apoptosis and Ferroptosis in AC16 Cells and HUVECs
AU - Wenlei Zhang
AU - Rui Duan
AU - Xinsheng Duan
AU - Sijing Tao
AU - Haoxuan Li
AU - Jinyan Li
AU - Xinru Wang
AU - Lijuan Yue
AU - Kai Ren
AU - Tianyu Zhao
AU - Meihua Guo
AU - Xiaoxiang Guan
AU - Xin Hai
PY - 2026
DA - 2026/09/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198753
UR - https://www.mdpi.com/1422-0067/27/19/8753
AB - Arsenic trioxide (ATO) is a first-line therapeutic agent for acute promyelocytic leukemia (APL), but its clinical utility is constrained by dose-dependent cardiotoxicity. This study aimed to systematically evaluate the cytoprotective potential of dihydroquercetin (DHQ), a natural flavonoid derived from coniferous species with multimodal antioxidant properties, against ATO-induced cellular injury. An integrated combining network pharmacology with experimental validation was employed to elucidate the underlying molecular mechanisms. Cardiotoxicity models were established using AC16 human cardiomyocytes and human umbilical vein endothelial cells (HUVECs). Cytotoxicity, reactive oxygen species (ROS), mitochondrial membrane potential, DNA damage (γ-H2AX), apoptosis (TUNEL, Bcl-2, Bax, Caspase-3), and ferroptosis markers (GPX4, xCT, intracellular iron) were assessed. The AMPK/SIRT1/PGC-1α axis was validated using Compound C. ATO exposure induced significant cytotoxicity, oxidative stress, mitochondrial dysfunction, and activated both apoptosis and ferroptosis pathways. Co-treatment with DHQ dose-dependently attenuated these injuries. Mechanistically, DHQ activated AMPK/SIRT1/PGC-1α, increasing phosphorylated AMPK, SIRT1, and PGC-1α. Compound C abrogated DHQ-mediated pathway activation and its protection against oxidative stress, apoptosis, and ferroptosis. DHQ protects against ATO cardiotoxicity by activating the AMPK/SIRT1/PGC-1α pathway, thereby reducing oxidative stress and concurrently inhibiting apoptosis and ferroptosis. These findings position DHQ as a promising candidate for protecting cardiomyocytes and endothelial cells from ATO-induced injury.
SN - 1422-0067
ER -