METTL3 dictates the development of thymocytes via restraining ferroptosis program during age related thymic involution

Thymic involution is a crucial factor in immune system aging and results in age-related impairment of T cell responses. The control of programmed cell death plays a fundamental role in thymocytes development. How thymocytes cell death contribute to thymic involution remains elusive. In this study, we found that METTL3 is highly expressed in double positive (DP) cells from young mice but decreased in aged mice. Mice conditionally deficiency for METTL3 in T cells showed thymic involution phenotypes with decreased survival and increased senescent DP cells. Additionally, METTL3 deficiency elicited ferroptosis program rather than other cell death pathways and led to defective DP cell development. Furthermore, GPX4, a molecule that protects cells from ferroptosis, was essential for thymocyte survival and preventing senescence. Mechanistically, GPX4 was maintained by METTL3 at the translation level in METTL3 methyltransferase activity independent manner. Targeting METTL3 and ferroptosis process promoted DP cell survival and reinvigorated aged DP cells. These findings reveal the central role of the METTL3-GPX4-ferroptosis axis in regulating thymocyte homeostasis and identifying targets for impeding age-related thymic involution and diseases.