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. 2023 Feb 1;9(5):eade9585. doi: 10.1126/sciadv.ade9585

Fig. 4. NRF2 regulates iron homeostasis through HERC2, VAMP8, and NCOA4.

Fig. 4.

NRF2 regulates iron homeostasis by controlling both ferritin synthesis and degradation. First, HERC2, an E3 ubiquitin ligase for FBXL5 and NCOA4, is an NRF2 target gene; deletion of NFE2L2/NRF2 results in reduced HERC2 expression, increased stability of FBXL5 and NCOA4, decreased IRP2 protein stability, and enhanced FTH synthesis. Second, NRF2 indirectly controls VAMP8 through the mTOR-TFEB axis. In NFE2L2/NRF2 KO cells, decreased TFEB-dependent transcription of VAMP8 results in blockage of autophagosome-lysosome fusion and inhibition of ferritinophagy. Third, excessive accumulation of NCOA4 in NFE2L2/NRF2 KO cells causes recruitment of apoferritin into autophagosomes, leading to autophagosomal accumulation of apoferritin/NCOA4, increased LIP, and enhanced sensitivity to ferroptotic cell death. Green dot, ferrous iron; red dot, ferric iron.