{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNuclear receptor coactivator 4 (NCOA4) is emerging as a multifunctional regulator of intracellular iron balance through its role as a selective cargo receptor that directs ferritin to the autophagy–lysosome pathway (ferritinophagy). By binding ferritin and facilitating its degradation, NCOA4 ensures the recycling of iron needed for critical cellular functions such as energy metabolism and red blood cell production. Dysregulation of this pathway can disturb iron homeostasis, leading to tissue iron accumulation and anemia under conditions of iron deprivation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its iron–recycling function, NCOA4 and related nuclear coactivators have been implicated in the regulation of nuclear receptor signaling and even DNA replication. Studies in mouse embryos have documented dynamic NCOA4 expression suggestive of roles in developmental transcriptional regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In parallel, investigations of androgen receptor–associated proteins (ARA70 isoforms) in prostate and breast cancer cells have demonstrated that distinct coactivator isoforms can differentially modulate hormone‐driven proliferation and tumor suppression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Moreover, direct interactions of NCOA4 with components of the DNA replication machinery, such as MCM7, reveal a checkpoint function where NCOA4 helps prevent unscheduled origin activation and replication stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA major emerging aspect of NCOA4’s function is its influence on ferroptosis, a form of iron–dependent cell death driven by lipid peroxidation. Enhanced NCOA4–mediated ferritinophagy increases the labile iron pool, thereby promoting oxidative damage in diverse pathological contexts including ischemic stroke"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", sepsis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and the development of anemia and ineffective erythropoiesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In addition, NCOA4 contributes to chondrocyte ferroptosis associated with osteoarthritis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and its actions are implicated in the pathogenesis of ischemic acute kidney injury by promoting ferritin degradation via interactions with immune signaling proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Altered ferritinophagy has also been observed in retinal injury"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", paraquat intoxication"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", and intestinal ischemia–reperfusion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Recent work further shows that post‐ischemic lactylation of NCOA4 in hippocampal neurons enhances its stability, thereby promoting both ferritinophagy and glycolysis that exacerbate cerebral injury"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", while a FOXO1–NCOA4 axis has been implicated in cisplatin–induced auditory neuron ferroptosis and associated hearing loss."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies underscore the tissue–specific regulation and broader impact of NCOA4 on cell fate. In the liver, NCOA4 facilitates the mobilization of iron stores following phlebotomy—a process regulated by hypoxia–inducible factors—to enable iron redistribution during stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " In parallel, investigations into hepatocyte senescence in non–alcoholic fatty liver disease suggest that alterations in autophagic processes, potentially linked to NCOA4 function, may contribute to degenerative changes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "William E Dowdle, Beat Nyfeler, Jane Nagel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb3053"}], "href": "https://doi.org/10.1038/ncb3053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25327288"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25327288"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Roberto Bellelli, Giorgia Federico, Alessandro Matte', et al. "}, {"type": "b", "children": [{"type": "t", "text": "NCOA4 Deficiency Impairs Systemic Iron Homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2015.12.065"}], "href": "https://doi.org/10.1016/j.celrep.2015.12.065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26776506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26776506"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Moon-Suhn Ryu, Deliang Zhang, Olga Protchenko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI90519"}], "href": "https://doi.org/10.1172/JCI90519"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28375153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28375153"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xiaofei Gao, Hsiang-Ying Lee, Wenbo Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1711058114"}], "href": "https://doi.org/10.1073/pnas.1711058114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28864529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28864529"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Antonella Nai, Maria Rosa Lidonnici, Giorgia Federico, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Haematologica (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3324/haematol.2019.241232"}], "href": "https://doi.org/10.3324/haematol.2019.241232"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32107334"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32107334"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Victoria Siriett, Gina Nicholas, Carole Berry, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Myostatin negatively regulates the expression of the steroid receptor co-factor ARA70."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.20456"}], "href": "https://doi.org/10.1002/jcp.20456"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16110473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16110473"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Martin Ligr, Yirong Li, Xuanyi Zou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor suppressor function of androgen receptor coactivator ARA70alpha in prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/ajpath.2010.090293"}], "href": "https://doi.org/10.2353/ajpath.2010.090293"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20167864"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20167864"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Alexandra Kollara, Theodore J Brown "}, {"type": "b", "children": [{"type": "t", "text": "Variable expression of nuclear receptor coactivator 4 (NcoA4) during mouse embryonic development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Histochem Cytochem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1369/jhc.2010.955294"}], "href": "https://doi.org/10.1369/jhc.2010.955294"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20354146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20354146"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Xinyu Wu, Fei Chen, Aysegul Sahin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct function of androgen receptor coactivator ARA70α and ARA70β in mammary gland development, and in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res Treat (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10549-010-1131-5"}], "href": "https://doi.org/10.1007/s10549-010-1131-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20814820"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20814820"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Roberto Bellelli, Maria Domenica Castellone, Teresa Guida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NCOA4 transcriptional coactivator inhibits activation of DNA replication origins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2014.04.031"}], "href": "https://doi.org/10.1016/j.molcel.2014.04.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24910095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24910095"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Chong Li, Guangchi Sun, Binglin Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear receptor coactivator 4-mediated ferritinophagy contributes to cerebral ischemia-induced ferroptosis in ischemic stroke."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacol Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.phrs.2021.105933"}], "href": "https://doi.org/10.1016/j.phrs.2021.105933"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34634471"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34634471"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Jie Wu, Qinjie Liu, Xufei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-022-05115-x"}], "href": "https://doi.org/10.1038/s41419-022-05115-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35902564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35902564"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Giorgia Federico, Federica Carrillo, Francesca Dapporto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NCOA4 links iron bioavailability to DNA metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2022.111207"}], "href": "https://doi.org/10.1016/j.celrep.2022.111207"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35977492"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35977492"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Kai Sun, Liangcai Hou, Zhou Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2023.03.008"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2023.03.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36907253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36907253"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Lini Jin, Binfeng Yu, Hongju Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STING promotes ferroptosis through NCOA4-dependent ferritinophagy in acute kidney injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2023.08.025"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2023.08.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37634745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37634745"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Xin Dong, Zijian Zhang, Nannan Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Novel Role of ARA70 in Regulating Ferritinophagy of RGCs During Retinal Ischemia Reperfusion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "DNA Cell Biol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/dna.2023.0077"}], "href": "https://doi.org/10.1089/dna.2023.0077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37903234"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37903234"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Zhenkai Ma, Hui Lu, Xuemin Feng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nrf2 protects against cartilage endplate degeneration through inhibiting NCOA4‑mediated ferritinophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2023.5339"}], "href": "https://doi.org/10.3892/ijmm.2023.5339"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38063237"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38063237"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Kun Li, Annan Wang, Yunpeng Diao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oxidative medicine and cellular longevity the role and mechanism of NCOA4 in ferroptosis induced by intestinal ischemia reperfusion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunopharmacol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.intimp.2024.112155"}], "href": "https://doi.org/10.1016/j.intimp.2024.112155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38688134"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38688134"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Xiaoyin He, Zhenzhen Wang, Qingbo Ge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lactylation of nuclear receptor coactivator 4 promotes ferritinophagy and glycolysis of neuronal cells after cerebral ischemic injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuroreport (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/WNR.0000000000002080"}], "href": "https://doi.org/10.1097/WNR.0000000000002080"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39166386"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39166386"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Xue Wang, Lei Xu, Yu Meng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FOXO1-NCOA4 Axis Contributes to Cisplatin-Induced Cochlea Spiral Ganglion Neuron Ferroptosis via Ferritinophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Sci (Weinh) (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/advs.202402671"}], "href": "https://doi.org/10.1002/advs.202402671"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39206719"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39206719"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Bingyu Li, Wei Wang, Yanan Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "cGAS-STING pathway aggravates early cerebral ischemia-reperfusion injury in mice by activating NCOA4-mediated ferritinophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Neurol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.expneurol.2022.114269"}], "href": "https://doi.org/10.1016/j.expneurol.2022.114269"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36343680"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36343680"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Xiaoyu Qi, Anping Song, Mingyue Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Curcumol inhibits ferritinophagy to restrain hepatocyte senescence through YAP/NCOA4 in non-alcoholic fatty liver disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Prolif (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cpr.13107"}], "href": "https://doi.org/10.1111/cpr.13107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34346124"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34346124"}]}]}]}