Differentiation Defect Repositions Sebaceous Glands as Instigators in the Early Pathogenesis of Hidradenitis Suppurativa

The role of sebaceous glands (SGs) in the early pathogenesis of hidradenitis suppurativa (HS) is undefined, with unclear causal relationship to inflammatory sequelae. The aim of this study was to determine whether SG aberrations constitute a primary pathogenic driver in early HS and elucidate the underlying mechanism. Histological study, single-cell RNA sequencing (scRNA-seq), and in vitro functional assays were employed. Clinical specimens included non-lesional skin, early lesional skin from patients diagnosed with Hurley I HS, and healthy controls. Human SZ95 sebocytes were used for mechanistic studies, including gene knockdown with lentivirus, bulk RNA sequencing, and liquid chromatography-tandem mass spectrometry based lipidomic analysis. 
The size of SG was significantly reduced in HS patients. Development aberration and significant downregulation of tight junction signaling (e.g., TJP1, OCLN, CLDN1) in HS SGs were revealed by scRNA-seq, associated with compromised barrier integrity and early CD45+ immune cell infiltration. Knockdown of CLDN1 in human SZ95 sebocytes recapitulated these findings, inducing a robust pro-inflammatory response and a shift toward keratinocyte-like lineage accompanied by metabolic reprogramming, specifically overproduction of lysophosphatidylcholine (LPC). Exogenous LPC directly promoted proliferation and inflammatory cytokine secretion in HaCaT keratinocytes. Collectively, these findings reposition SGs as instigators in the early pathogenesis of HS.