Differentiation defects reposition sebaceous glands as inflammatory instigators in the early pathogenesis of hidradenitis suppurativa

<h4>Background</h4>The role of sebaceous glands (SGs) in the early pathogenesis of hidradenitis suppurativa (HS) remains undefined, with an unclear causal relationship to inflammatory sequelae. The aim of this study is to determine whether SG aberrations constitute a primary pathogenic driver in early HS and elucidate the underlying mechanisms.<h4>Methods</h4>We employed histology, single-cell RNA sequencing, and <i>in-vitro</i> functional assays. Clinical specimens included non-lesional skin (NLS, <i>n</i> = 6), early lesional skin (LS, Hurley I, <i>n</i> = 12) from HS patients, and healthy controls (HC, <i>n</i> = 8). Human SZ95 sebocytes were used for mechanistic studies, including gene knockdown, bulk RNA sequencing, and lipidomic analysis.<h4>Results</h4>SG size was significantly reduced in both NLS (47.26% of HC area, <i>p</i> = 0.04) and LS (30.74%, <i>p</i> = 0.006). Single-cell RNA sequencing analysis revealed aberrant stem cell commitment in the hair follicle junctional zone and a significant downregulation of tight junction signaling (e.g., CLDN1, TJP1, OCLN) in HS SGs, associated with compromised barrier integrity and early immune cell (CD45⁺) infiltration. CLDN1 knockdown in SZ95 sebocytes recapitulated these findings, inducing a robust pro-inflammatory response (upregulation of IL-1β, TNF-α, IL-6, S100A7/A8, and CXCL8), suppression of the sebocyte lineage regulator c-Myc, and a shift toward keratinocyte-like differentiation. This was accompanied by metabolic reprogramming, specifically overproduction of lysophosphatidylcholine (LPC). Exogenous LPC directly promoted proliferation and inflammatory cytokine secretion in HaCaT keratinocytes.<h4>Conclusions</h4>SG dysfunction, initiated by tight junction disruption and CLDN1 deficiency, is a primary event in early HS. This leads to aberrant sebocyte differentiation, inflammatory amplification, and sebum metabolite LPC-mediated crosstalk with keratinocytes. Our findings position SG-derived LPC as a potential novel biomarker and therapeutic target in HS pathogenesis.