Spatial Metabolism of Primary Limited Cutaneous Amyloidosis Based on Mass Spectrometry Imaging

Primary limited cutaneous amyloidosis (PLCA) is characterized by the amyloid deposition in the skin without systemic involvement. However, the precise composition and mechanisms underlying amyloid formation remain incompletely understood. In this study, skin tissues of PLCA and healthy controls (HC) were stained with Congo red and subsequently segmented based on staining patterns. Mass spectrometry imaging (MSI) was employed to analyze the spatial distribution of metabolites across these defined regions. By integrating variable importance in projection (VIP) values, folding changes (FC), and the biological functions of metabolites, several metabolites potentially linked to amyloid deposition in PLCA were identified from a pool of 1941 detected metabolites. Notably, elevated levels of arginine and its derivatives, lipoic acid, dihydrolipoic acid, and pyruvate were found in PLCA. KEGG pathway analysis revealed significant enrichment of the arginine biosynthesis pathway. Furthermore, immunohistochemical and RNA sequencing analyses demonstrated upregulated expression of arginase 1 (ARG1), an enzyme involved in arginine catabolism, in PLCA lesions. Subsequent in vitro studies indicated that arginine promoted the proliferation of HaCaT cells and upregulated keratin 5 (K5) expression, potentially implicating these processes in PLCA pathogenesis. Based on these findings, we propose that metabolic dysregulation-particularly in arginine metabolism-may play an important role in the pathogenesis of PLCA, providing new insights into the molecular mechanisms underlying this condition.