Mesencephalic astrocyte-derived neurotrophic factor suppresses ferroptosis to alleviate depressive-like behaviors via the PERK/ATF4 signaling pathway.

Ferroptosis is being increasingly implicated in the pathophysiology of major depressive disorder (MDD). Endoplasmic reticulum (ER) stress is closely linked to ferroptosis, yet the endogenous regulators connecting ER dysfunction to ferroptosis during chronic stress remain unclear. Here, we report that the expression of mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER stress-inducible protein, was upregulated in the hippocampus (Hip) of male mice subjected to chronic social defeat stress (CSDS). Hippocampal MANF overexpression alleviated depressive-like behaviors and suppressed ferroptosis, whereas MANF knockdown promoted stress susceptibility and facilitated ferroptosis. Ferrostatin-1 (Fer-1) mimicked the protective effects of MANF overexpression and rescued MANF deficiency-induced phenotypes. Mechanistically, MANF inhibited PERK/ATF4 signaling, and overexpression of PERK or ATF4 partially counteracted MANF-mediated protection, whereas their knockdown rescued MANF deficiency-induced phenotypes. Furthermore, ATF4 increased the promoter activity of glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) in an ATF4-binding-site-dependent manner, thereby impairing the SLC7A11/GPX4 anti-ferroptotic defense axis and driving ferroptosis. These findings identify hippocampal MANF as an endogenous protective factor that suppresses stress-induced ferroptosis through the PERK/ATF4 pathway and position MANF as a potential therapeutic target for MDD.