Lipid Metabolic Dysregulation Driven by OSMR Mutations Underlies Amyloidogenesis in Primary Localized Cutaneous Amyloidosis.

BACKGROUND

Primary localized cutaneous amyloidosis (PLCA) is characterized by the deposition of amyloid material within the superficial dermis. Its origin and composition remain debated, including whether deposits derive from keratin filament degeneration or misfolded protein aggregation, and whether non-protein components contribute.

OBJECTIVES

This study aimed to re-examine the composition of PLCA deposits and elucidate how OSMR mutations drive their formation, focusing on protein aggregation and lipid metabolism.

METHODS

We employed PROTEOSTAT staining, lipidomics, and Nile Red/Oil Red O staining in patient tissues, engineered HaCaT cells, and mouse models, together with mechanistic functional analyses.

RESULTS

PLCA lesions contain abundant protein aggregates alongside significant lipid accumulation, indicating pathological protein-lipid complexes. As the common genetic defect in familial PLCA, OSMRβ deficiency significantly promoted both lipid accumulation and protein aggregation in cellular and animal models. Lipidomic profiling revealed alterations in unsaturated fatty acids (UFAs, C18:1/C18:2) and ceramides. Crucially, exogenous UFAs induced protein aggregation. Mechanistically, OSMRβ deficiency impairs STAT5 activation, leading to AKR1B10 upregulation and lipid dysregulation, whereas inhibition of this axis rescued both phenotypes.

CONCLUSIONS

OSMR mutation drives amyloid deposition in PLCA through a STAT5-AKR1B10 lipid metabolic axis that promotes co-aggregation of lipids and misfolded proteins, providing potential therapeutic targets.