Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development

The development of functional neurons is a complex orchestration of multiple signaling pathways that control cell proliferation, differentiation, and homeostasis, the details of which are not fully understood. Because the balance of antioxidants and vitamins is important for neuronal survival and development, we hypothesized that ferroptosis (a cell death modality controlled by antioxidants) must be suppressed to gain neurons. We found that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids. However, impaired neuronal development in conditions lacking antioxidants could be fully restored when ferroptosis was specifically inhibited by ferrostatin-1 or when neuronal differentiation occurred in the presence of vitamin A. We determined that all-trans retinoic acid (ATRA), the active metabolite of vitamin A, activates the heterodimeric nuclear receptor complex Retinoic Acid Receptor (RAR)/Retinoid X Receptor (RXR), which orchestrates the increased expression of the ferroptosis inhibitors GPX4, FSP1, GCH1, and ACSL3, amongst others. In contrast, retinal and retinol have radical-trapping functions. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.