Lesional hair lipidomic signatures reveal ARA-LTB4 pathway activation and NETs formation in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory disease originating from the folliculosebaceous unit (FPSU), characterized by abundant neutrophil infiltration in the skin. We aimed to address the lack of systemic evidence regarding lipid metabolic dysregulation within the FPSU in disease pathogenesis. By integrating the lipidomic features of lesional hair, skin tissue, and pus, we found prominent dysregulation of arachidonic acid (ARA) and leukotriene B4 (LTB4) across all specimens. Notably, the lipidomic features in lesional hair directly correlated with disease severity. Mechanistically, HS lesions exhibited activation of a bacterial-keratinocyte-neutrophil cascade, in which sustained exposure to lipopolysaccharide (LPS) derived from Gram-negative bacteria induced phosphorylation of cytosolic phospholipase A2α (cPLA2α) in keratinocytes. This response was further amplified by recruited neutrophils through 5-lipoxygenase (5-LO) activation, resulting in increased production of LTB4 and extensive neutrophil extracellular traps (NETs) formation. These findings were further validated in NcstnΔCKO mice, where lipid profiles in lesional hair mirrored those of HS patients. Our study provided evidence that lipid mediators in HS lesional hair served as sensitive markers for disease activity, suggesting that targeting Gram-negative colonization or the ARA-LTB4 pathway represented a promising therapeutic intervention for HS.