biostudies-literatureHaggerty NRNIEHS NIH HHS110707https://www.ebi.ac.uk/biostudies/studies/S-EPMC12596596biostudies-literatureUnknown301(11)The primary mechanism that controls manganese (Mn) homeostasis in mammals is the activation of hypoxia-inducible factor (HIF) transcription factors by elevated Mn, which transcriptionally upregulates expression of the Mn efflux transporter SLC30A10 to reduce cellular/organismal Mn levels. Here, we identify an additional unexpected component of the Mn-induced and HIF-dependent homeostatic response that represses SLC30A10 expression. In cells, (1) Mn treatment upregulated expression of the transcription factor NR4A1 (also called Nur77); (2) NR4A1 knockdown increased SLC30A10 expression and reduced the sensitivity of wildtype, but not ΔSLC30A10, cells to Mn toxicity; and (3) overexpression of NR4A1 reduced SLC30A10 expression and increased sensitivity to Mn toxicity. Thus, NR4A1 is a Mn-respoThe Journal of biological chemistryNR4A1 is a HIF-dependent repressor of SLC30A10 transcription that controls manganese homeostasis.PMC12596596R01 ES031574R01 ES024812Sharma NLee YRSmith DRHaggerty NRJursa TMukhopadhyay SfalseNR4A1 is a HIF-dependent repressor of SLC30A10 transcription that controls manganese homeostasis.The primary mechanism that controls manganese (Mn) homeostasis in mammals is the activation of hypoxia-inducible factor (HIF) transcription factors by elevated Mn, which transcriptionally upregulates expression of the Mn efflux transporter SLC30A10 to reduce cellular/organismal Mn levels. Here, we identify an additional unexpected component of the Mn-induced and HIF-dependent homeostatic response that represses SLC30A10 expression. In cells, (1) Mn treatment upregulated expression of the transcription factor NR4A1 (also called Nur77); (2) NR4A1 knockdown increased SLC30A10 expression and reduced the sensitivity of wildtype, but not ΔSLC30A10, cells to Mn toxicity; and (3) overexpression of NR4A1 reduced SLC30A10 expression and increased sensitivity to Mn toxicity. Thus, NR4A1 is a Mn-respo2025-01-01T00:00:00Z2025 Sep2026-06-05T13:04:09.598Z2026-05-17T03:13:23.965ZS-EPMC125965964094572210.1016/j.jbc.2025.110707