DHA and EPA exacerbate hypoxia-induced ferroptosis in gastric and small intestinal mucosa by disrupting the balance between SLC7A11 upregulation and PUFA-PL accumulation.

Hypoxia, resulting from environmental factors or diseases, can disrupt the gastrointestinal mucosal barrier. Our previous study demonstrated that hypoxia induced ferroptosis in the gastric and small intestinal mucosa by upregulating ALOX5, NOX4, and polyunsaturated fatty acid-containing phospholipids (PUFA-PLs). The impact of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on ferroptosis is currently a subject of debate. While DHA and EPA upregulate SLC7A11 expression, mitigating lipid peroxidation, they also elevate PUFA-PL levels, exacerbating it. This study investigated the effects and underlying mechanisms of DHA and EPA supplementation on gastric and small intestinal mucosal ferroptosis under normoxic and hypoxic conditions in vitro and in vivo. Under normoxia, DHA and EPA upregulated SLC7A11 expression through the cAMP/PKA/ATF3 pathway, thereby enhancing cellular resistance to lipid peroxidation associated with increased PUFA-PL levels and preventing ferroptosis. In contrast, under hypoxia, DHA and EPA exacerbated ferroptosis by further increasing PUFA-PL levels, which, in combination with hypoxia-induced ALOX5 and NOX4 expression, resulted in excessive lipid peroxidation that overwhelmed the protective mechanisms mediated by SLC7A11 upregulation. These findings indicate that DHA and EPA exacerbate hypoxia-induced ferroptosis in gastric and small intestinal mucosa. Therefore, individuals at risk of hypoxia should carefully consider the potential risks associated with DHA and EPA intake.