Remodeling of ferroptotic necroinflammation by dexamethasone in acute tubular necrosis.

Abstract

Ferroptosis, a modality of regulated necrosis caused by iron-dependent lipid peroxidation, has emerged as a key contributor to the pathogenesis of acute tubular necrosis (ATN) - especially in the context of solid organ transplantation. While recent studies have identified hormones as extracellular signals that modulate cellular susceptibility to ferroptosis, their pathophysiological relevance in vivo remains incompletely defined. Here, we investigated the role of dexamethasone, a potent synthetic glucocorticoid previously reported to sensitize cells to ferroptosis, in the context of renal tubular injury. Unexpectedly, we observed a biphasic effect: early sensitization to ferroptosis induced by glutathione depletion was subsequently counteracted by a marked increase in ferroptosis resistance. Mechanistically, we found that dexamethasone reduced availability of ferrous iron via effects of the glucocorticoid receptor 1 (GR1), which also resulted in attenuated renal tubular injury. However, this cytoprotective effect did not translate into improved renal function, as dexamethasone exerted additional ferroptosis-independent effects on innate immune cell recruitment to injured kidneys. Collectively, our findings highlight the highly dynamic nature of the ferroptotic process in which modulatory signals can exert temporally opposing effects. Moreover, they underscore the complex interplay between regulated cell death and innate immune responses in shaping necroinflammation in disease trajectories.