Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor–induced dipeptidase-1 expression and glutathione depletion

Abstract

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)–dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.

Black pepper oil (Piper nigrum L.) mitigates dexamethasone induced pancreatic damage via modulation of oxidative and nitrosative stress

“…Dexamethasone is reported to induce oxidative stress in skeletal muscles directly through binding to the glucocorticoid receptors and in pancreas, via deactivating PI3K/Akt/Nrf2 signaling pathways, and by inducing glucotoxicity of pancreatic islets [56] , [12] . Furthermore, a recent study showed that dexamethasone causes GSH depletion and induces ferroptosis in HT1080 cells in a glucocorticoid receptor dependent manner [2] . This may explain the effects of dexamethasone on the oxidative stress markers observed in the current study.…”

“…Glucocorticoids are commonly utilized to treat a variety of disorders and recognized among the highly effective anti-inflammatory and immunosuppressive medications [1] . Dexamethasone belongs to this drug family and has recently been widely approved to treat the hospitalized, critically ill patients with coronavirus disease 2019 (COVID 19) [2] . However, glucocorticoids are linked to variety of adverse effects, such as new onset hyperglycemia in patients without diabetes mellitus (DM) history or hard-to-control hyperglycemia in people with DM.…”

Ferroptosis in inflammatory arthritis: A promising future

“…Dexamethasone (DXMS) can induce ferroptosis via P53/SLC7A11/GPX4 pathway in pre-osteoblast MC3T3-E1 cells and osteocyte MLOY4 cells in glucocorticoid-induced osteonecrosis ( 75 ). DXMS could reduce GSH by upregulating the expression of dipeptidase-1 (DPEP1) to increase the sensitivity to ferroptosis in HT1080 cells, and prednisolone was found to have a similar effect on ferroptosis-sensitivity-increasing effect in the study ( 74 ).…”

Regulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections

“…Several studies showed the potential of dexamethasone in modulating cell death, like regulated necrosis. Very recently, it has been proved that dexamethasone sensitizes erastin-induced ferroptosis via glutathione depletion [ 88 ]. Dexamethasone can also alleviate corneal alkali injuries by inhibiting the caspase-1/GSDMD-mediated pyroptotic signaling pathway [ 89 ].…”