4.4 Article

Insufficient autophagy enables the nuclear factor erythroid 2-related factor 2 (NRF2) to promote ferroptosis in morphine-treated SH-SY5Y cells

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PSYCHOPHARMACOLOGY
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SPRINGER
DOI: 10.1007/s00213-023-06485-6

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Morphine; Ferroptosis; Insufficient autophagy

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This study aims to clarify the role of opioid receptors in morphine-induced ferroptosis and investigate the role of NRF2 in morphine-induced ferroptosis. The results showed that morphine can induce ferroptosis in a dose-dependent manner, and GPX4 may be involved in this process. Additionally, NRF2 was found to promote morphine-induced ferroptosis, possibly due to increased p62-related insufficient autophagy.
RationaleWhile morphine has important therapeutic value it is also one of the most widely abused drugs in the world. As a newly discovered style of cell death, ferroptosis is involved in the occurrence and development of many diseases, however, the current understanding of the relationship between ferroptosis and morphine is still limited.ObjectiveTo clarify the role of opioid receptors in morphine-induced ferroptosis and to investigate the role of NRF2 in morphine-induced ferroptosis.MethodsWe first used different doses of morphine (0, 0.5, 1, and 1.5 mM) to investigate morphine-induced ferroptosis in SH-SY5Y cells, and we choose 1.5 mM morphine for subsequent experiments. We next inhibited opioid receptors and NRF2 separately and examined their influence on morphine-induced ferroptosis. Finally, we tested morphine-induced insufficient autophagy.ResultsMorphine triggered ferroptosis in a dose-dependent manner, which could be significantly rescued by the ferroptosis-specific inhibitor DFO. Moreover, GPX4 rather than xCT antiporter might be involved in morphine-induced ferroptosis. We also found naloxone could inhibit morphine-induced ferroptosis. Interestingly, our results demonstrated that NRF2 could promote rather than defend morphine-induced ferroptosis; this may be due to the increased p62-related insufficient autophagy.ConclusionMorphine-induced ferroptosis is regulated by the opioid receptor and GPX4 rather than the xCT antiporter. NRF2-mediated ferroptosis in morphine-exposed cells may stem from increased p62-related insufficient autophagy.

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