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Ferroptosis is a regulated form of cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Ceruloplasmin (CP) is a glycoprotein that plays an essential role in iron homeostasis. However, whether CP regulates ferroptosis has not been reported. Here, we show that CP suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma (HCC) cells. Depletion of CP promoted erastin- and RSL3-induced ferroptotic cell death and resulted in the accumulation of intracellular ferrous iron (Fe2+) and lipid reactive oxygen species (ROS). Moreover, overexpression of CP suppressed erastin- and RSL3-induced ferroptosis in HCC cells. In addition, a novel frameshift mutation (c.1192-1196del, p.leu398serfs) of CP gene newly identified in patients with iron accumulation and neurodegenerative diseases lost its ability to regulate iron homeostasis and thus failed to participate in the regulation of ferroptosis. Collectively, these data suggest that CP plays an indispensable role in ferroptosis by regulating iron metabolism and indicate a potential therapeutic approach for hepatocellular carcinoma.
Pubmed ID: 32283255 RIS Download
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Recently, our team completed an NINDS-funded, Phase IIa double-blinded, placebo-controlled pilot clinical trial that examined the pharmacokinetics, safety, and activity of progesterone, a steroid found to have powerful neuroprotective effects in multiple animal models of brain injury. Our pilot study demonstrated a 50% reduction in death among severe TBI patients and less disability among moderate TBI patients treated with progesterone. Based on these promising results and supportive preclinical data, we are conducting a large, phase III clinical trial (ProTECT III) to definitively assess the safety and efficacy of this treatment for adults with moderate to severe acute TBI. The study is slated to begin August 2008. WHY Progesterone: Although progresterone is widely considered a sex steroid, it is also a potent neurosteroid. Progesterone is naturally synthesized in the CNS. A large and growing body of animal studies indicate that early administration of progesterone after TBI reduces cerebral edema, neuronal loss, and behavioral deficits in laboratory animals. Certain properties of progesterone make it an ideal therapeutic candidate. First, in contrast to most drugs tested to date, progesterone rapidly enters the brain and reaches equilibrium with the plasma within an hour of administration. Second, unlike other experimental agents, progesterone has a long history of safe use in humans. Finally, the findings of our pilot clinical trial (presented in the Preliminary Data Section, below) indicate that progesterone has consistent and predictable pharmacokinetic properties, is unlikely to produce harm, and may be efficacious for treating acute TBI in humans.
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