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Differentiation defects reposition sebaceous glands as inflammatory instigators in the early pathogenesis of hidradenitis suppurativa
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DOI：10.3389/fimmu.2026.1785747.png)
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Abstract
En 中文
BackgroundThe 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.MethodsWe employed histology; single-cell RNA sequencing; and in-vitro functional assays. Clinical specimens included non-lesional skin (NLS; n = 6); early lesional skin (LS; Hurley I; n = 12) from HS patients; and healthy controls (HC; n = 8). Human SZ95 sebocytes were used for mechanistic studies; including gene knockdown; bulk RNA sequencing; and lipidomic analysis.ResultsSG size was significantly reduced in both NLS (47.26% of HC area; p = 0.04) and LS (30.74%; p = 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.ConclusionsSG 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.
Keywords:
sebum
tight junction
lysophosphatidylcholine
Hidradenitis suppurativa
sebaceous gland
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