Hydrogen sulfide antagonizes formaldehyde-induced ferroptosis via preventing ferritinophagy by upregulation of GDF11 in HT22 cells

Formaldehyde (FA) has neurotoxic characteristics and causes neurodegenerative disease . Our previous study demonstrated the neuroprotective effects of hydrogen sulfide (H 2 S) on FA-induced neurotoxicity in HT22 cells. Emerging evidence have supported that ferroptosis is involved in FA-induced neurotoxicity. To understand the mechanism of the protection of H 2 S against FA-induced neurotoxicity, this study explored the regulatory effect of H 2 S on FA-induced ferroptosis and the underlying mechanisms. We found that H 2 S (100, 200, and 400?μM, 30?min) reverses the ferroptosis induced by FA (100?μM, 24?h) in HT22 cells (a cell line of mouse hippocampal neurons), including decreases in free iron, reactive oxygen species (ROS), 4-hydroxy-2-trans-nominal (4-HNE), and malondialdehyde (MDA) contents, as well as an increase in glutathione (GSH) content. H 2 S (100, 200, and 400?μM, 30?min) also inhibited ferritinaphagy in FA-exposed HT22 cells, as evidenced by the downregulation of the ferritinophagy receptor nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain-3B (LC3B) as well as the upregulation of the main iron storage protein ferritin heavy chain 1 (FTH1) and p62. H 2 S (100, 200, and 400?μM, 30?min) also up-regulated the expression of growth differentiation factor-11 (GDF11) in FA-exposed HT22 cells. Furthermore, knockdown of GDF11 in HT22 cells cancelled the beneficial effects of H 2 S on FA-induced ferroptosis and ferritinaphagy. These data indicated that the protective mechanism underlying H 2 S-prevented neurotoxicity of FA is involved in alleviating FA-induced ferroptosis via inhibiting ferritinaphagy by upregulation of GDF11.

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