Metabolic and Vascular Inflammation in Alopecia Areata: Linking Uric Acid, Lipid Imbalance and ICAM-1 Upregulation

Alopecia areata (AA) is an inflammatory hair loss disorder caused by an immune-mediated attack of the hair follicle (HF) bulb. Active disease is characterised by a peribulbar proinflammatory infiltrate, HF immune privilege collapse and premature catagen induction, yet the underlying drivers of AA remain poorly understood. With comparable autoimmune inflammatory conditions displaying metabolic alterations, we hypothesised that AA is marked by similar pathobiological changes. To investigate this, we utilised an exploratory metabolomics-based discovery liquid chromatography mass spectrometry (LC-MS) approach. This yielded 32 putatively annotated metabolites significantly altered between lesional and nonlesional AA scalp. Notably, 13-HODE, a linoleic acid metabolite linked to vascular function, was decreased, whilst uric acid (UA), a purine degradation metabolite linked to vascular dysfunction, was increased in the lesional scalp. Moreover, serum LC-MS revealed elevated UA in AA compared to controls, which is linked to systemic endothelial dysfunction. CD31+/ICAM-1+ immunofluorescence co-expression analysis revealed elevated vascular inflammation and endothelial cell activation in the AA scalp. We also experimentally provoked the same response in ex vivo human HF culture via UA or fructose (which increases UA) supplementation. Interestingly, the fructose-generating polyol pathway enzymes, AKR1B1 and SORD, are expressed in the HF, with significantly increased AKR1B1 immunoreactivity in lesional AA HFs, suggesting that fructose can be locally generated by the HF and may contribute to elevated UA levels in AA. Together, these metabolic changes point towards UA-linked microvascular dysfunction in AA, inviting exploration of whether strategies to improve endothelial function and regulate UA are effective in managing AA.