METTL3 governs thymocyte development and thymic involution by regulating ferroptosis.

Area of Science:

• Immunology
• Aging Research
• Cell Biology

Background:

• Thymic involution, a hallmark of immune aging, involves complex cellular processes.
• The precise role of cell death pathways, particularly ferroptosis, in thymic involution remains largely unknown.
• Identifying regulators of thymic involution is crucial for understanding and potentially mitigating immune decline.

Purpose of the Study:

• To investigate the role of methyltransferase-like protein 3 (METTL3) in thymic involution.
• To elucidate the mechanisms by which METTL3 influences thymocyte survival and aging.
• To explore therapeutic strategies targeting ferroptosis for restoring thymic function.

Main Methods:

• Analysis of CD4+CD8+ double-positive (DP) thymocytes in aged mice.
• Conditional deletion of METTL3 in T cells.
• Assessment of ferroptosis signaling and glutathione peroxidase 4 (GPX4) levels.
• Pharmacological inhibition of ferroptosis.

Main Results:

• Aged DP thymocytes exhibit senescence and reduced METTL3 expression.
• METTL3 deficiency in T cells exacerbates DP thymocyte aging and promotes ferroptosis.
• METTL3 maintains GPX4 at the translational level, independent of its methyltransferase activity.
• Inhibition of ferroptosis rescues DP cell survival and attenuates aging features.

Conclusions:

• METTL3 plays a critical role in preventing ferroptosis and restraining thymic involution.
• METTL3 regulates GPX4 translation, thereby controlling ferroptosis in DP thymocytes.
• Targeting METTL3-regulated ferroptosis presents a potential strategy to restore thymic function in aging individuals.