BECN1 regulates ferroptosis induced by 2,4-dichlorophenoxyacetic acid in SH-SY5Y cells
2,4-Dichlorophenoxyacetic acid (2,4-D), the most widely used herbicide globally, has raised considerable concern due to its harmful effects on organisms. Exposure to 2,4-D induces ferroptosis, a form of programmed cell death driven by oxidative stress. BECN1, a key autophagy protein, is linked to fe...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
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| Series: | Ecotoxicology and Environmental Safety |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325007638 |
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| Summary: | 2,4-Dichlorophenoxyacetic acid (2,4-D), the most widely used herbicide globally, has raised considerable concern due to its harmful effects on organisms. Exposure to 2,4-D induces ferroptosis, a form of programmed cell death driven by oxidative stress. BECN1, a key autophagy protein, is linked to ferroptosis. This study examined ferroptosis mediated by the Xc－/GSH/GPX4 axis in 2,4-D-induced neurotoxicity using SH-SY5Y cells. These cells were treated with 0, 400, 800, or 1600 μmol/L 2,4-D, both with and without ferrostatin-1 (1.0 μmol/L) or BECN1-siRNA (100 pmol/μL). The results demonstrated that 2,4-D exposure increased malondialdehyde (MDA) and reactive oxygen species (ROS) levels while simultaneously decreasing superoxide dismutase (SOD) and glutathione (GSH) levels. Transmission electron microscopy (TEM) showed ferroptosis, elevated levels of ferrous ion (Fe2+) solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4), along with decreased ferritin protein and mRNA levels and increased transferrin receptor 1 (TFR1) protein and mRNA levels). The Ferrostatin-1 + 2,4-D group reduced intracellular MDA and ROS levels and increased SOD and GSH levels. In contrast, the siRNA-BECN1 + 2,4-D group exhibited attenuated oxidative damage, decreased Fe2+ ion content, and increased levels of SLC7A11, GPX4, and ferritin. TEM also showed reduced ferroptosis in the Ferrostatin-1 + 2,4-D group. In conclusion, 2,4-D induces oxidative stress and ferroptosis. Ferroptosis inhibitor ferrostatin-1 and siRNA transfection, which inhibit BECN1 expression, could alleviate 2, 4-D-induced oxidative stress and mitigate the ferroptosis phenomenon, thus playing a neuroprotective role. Our results provide a basis for the future development of preventive and therapeutic strategies against neurotoxicity caused by 2,4-D exposure. |
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| ISSN: | 0147-6513 |