Study On The Mechanism Of Glucocorticoid Drug Mometasone Furoate Regulating Ferroptosis

Glucocorticoid is an important steroid hormone with the ability to regulate sugar,fat,protein biosynthesis and metabolism,and also have anti-inflammatory,antiviral,anti-shock,and immunosuppressive effects.Endogenous corticosteroids originate from the adrenal glands and are secreted by adrenal cortical cells in circadian rhythms.Due to the short biological halflife of endogenous glucocorticoids,a series of synthetic glucocorticoids have been developed,such as betamethasone,dexamethasone,mometasone furoate.Glucocorticoids are widely used in the treatment of various respiratory diseases,severe acute infections or inflammation,autoimmune and allergic diseases.In addition,it is also widely used in tumor treatment,especially lymphatic malignant tumors,glucocorticoids can significantly inhibit the proliferation and metastasis of lymphatic system tumors.But in the treatment of other types of tumors,glucocorticoids are mainly used to counteract the adverse reactions and toxicity of radiotherapy and chemotherapy,such as nausea,vomiting,anorexia,bone marrow suppression,cancer pain,adrenal insufficiency,superior vena cava syndrome and other symptoms.However,some clinical statistics have suggested that glucocorticoids may lead to a significant reduction in overall survival,suggesting that we need to re-understand the role of glucocorticoids in tumor treatment.Ferroptosis is a novel programmed cell death,which is different from apoptosis,necrosis,autophagy in morphology,biochemical characteristics,and mechanistic pathways.In morphology,it is mainly manifested as a smaller mitochondria and an increase in membrane density.In terms of biochemical characteristics,it is mainly manifested as iron aggregation,glutathione depletion,and the occurrence of lipid peroxidation.Ferroptosis is regulated by intracellular signaling pathways,mainly including iron homeostasis,cystine transport,and lipid peroxidation.SLC7A11-mediated cystine transport is the rate-limiting step for glutathione synthesis,thereby blocking glutathione synthesis sensitizes cells to ferroptosis,so SLC7A11 is a key gene in defending ferroptosis.In recent years,more and more studies have found that tumor cells have a unique metabolic network and a high-load reactive oxygen environment,making them more prone to ferroptosis,so ferroptosis has great potential in the treatment of tumor.Our study found that the glucocorticoid drug mometasone furoate can significantly inhibits ferroptosis of tumor cells and promotes tumor cell survival.In addition,two other glucocorticoids,betamethasone and dexamethasone,can also suppress ferroptosis to a weaker extent.Mechanistically,mometasone furoate remarkedly upregulates SLC7A11 to protect tumor cells from ferroptosis.Previous studies have found that glucocorticoids play the role dependent of glucocorticoid receptor NR3C1.However,our data revealed that the mometasone furoate-mediated SLC7A11 upregulation is independent of NR3C1.In addition,it has been reported that glucocorticoids regulate ferroptosis through NRF2 pathway,whereas our study showed that deficiency of NRF2 does not impair the effect of mometasone furoate.Although the mechanism of upregulation of SLCA711 by mometasone furoate is not well understood,our results suggest that the glucocorticoid drug MF could promote tumor survival by upregulating SLC7A11 to rescue ferroptosis,so it should be used with caution during tumor treatment.