Hepcidin regulates neuronal ferroptosis: A mechanism for postoperative cognitive dysfunction

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Postoperative cognitive dysfunction (POCD) is a common complication, particularly in aged individuals.
• Toll-like receptor 4 (TLR4) signaling, involving myeloid differentiation protein 2 (MD2), plays a role in inflammatory responses.
• Neurocyte ferroptosis, an iron-dependent form of cell death, is increasingly implicated in neurological disorders.

Purpose of the Study:

• To investigate the role of MD2 in regulating neurocyte ferroptosis.
• To explore the association between MD2-mediated ferroptosis and the development of POCD.
• To assess the therapeutic potential of targeting MD2 for POCD.

Main Methods:

• Aged wild-type (Wt) and MD2 transgenic (Tg) mice underwent splenectomy to induce POCD.
• Neurocognitive function was assessed using the Morris water maze.
• Histopathology, Nissl staining, Western blotting, immunohistochemistry, and biochemical assays (Fe2+, SOD, MDA, GSH, GPX4) were employed to evaluate neurocyte damage, ferroptosis markers, and protein expression (TFR, Hepc, MD2).

Main Results:

• Tg-POCD mice exhibited exacerbated POCD and neurocyte damage compared to Wt-POCD mice.
• Increased Fe2+ and MDA levels, alongside decreased SOD, GSH, and GPX4, indicated significant ferroptosis in Tg-POCD mice.
• Inhibition of MD2 in Tg mice significantly ameliorated POCD, reduced ferroptosis markers, and restored cellular antioxidant capacity.

Conclusions:

• MD2 promotes neurocyte ferroptosis by regulating hepcidin (Hepc) expression.
• MD2-induced ferroptosis is a key mechanism contributing to POCD.
• Targeting MD2 presents a promising therapeutic strategy for mitigating POCD.