Beyond Barrier-Centric Models: Framing Steroid-Induced Skin Atrophy as a Vascular–Metabolic Failure

This paper reframes steroid-induced skin atrophy as a primary vascular–metabolic failure state, driven by glucocorticoid receptor–mediated suppression of microvascular signaling. Integrating glucocorticoid pharmacodynamics, pericyte biology, calcium and nitric oxide signaling, and molecular stress pathways, the analysis positions sustained pericyte-mediated vasoconstriction, metabolic suppression, and tissue hypoxia as the initiating events. Barrier impairment is shown to arise downstream as an epiphenomenon of energetic insufficiency rather than as the primary pathology.

Particular focus is placed on the roles of REDD1 (DDIT4) and FKBP51 as glucocorticoid-induced metabolic regulators linking steroid exposure to hypoxia, mTOR/Akt suppression, and proliferative arrest. Experimental evidence demonstrating preservation of dermal and epidermal structure through modulation of vascular–metabolic signaling—without loss of anti-inflammatory efficacy—supports a causal locus upstream of barrier architecture.

By reclassifying steroid-induced skin atrophy as a vascular–metabolic regulatory failure rather than a barrier disorder, this work resolves longstanding inconsistencies in the literature, clarifies the mechanism underlying rebound phenomena, and provides a coherent systems-level foundation for safer glucocorticoid design and assessment.