{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T04:58:55Z","timestamp":1780894735987,"version":"3.54.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed histology, single-cell RNA sequencing, and\n                      <jats:italic>in-vitro<\/jats:italic>\n                      functional assays. Clinical specimens included non-lesional skin (NLS,\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a06), early lesional skin (LS, Hurley I,\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a012) from HS patients, and healthy controls (HC,\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a08). Human SZ95 sebocytes were used for mechanistic studies, including gene knockdown, bulk RNA sequencing, and lipidomic analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SG size was significantly reduced in both NLS (47.26% of HC area,\n                      <jats:italic>p<\/jats:italic>\n                      =\u00a00.04) and LS (30.74%,\n                      <jats:italic>p<\/jats:italic>\n                      =\u00a00.006). 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\n                      <jats:sup>+<\/jats:sup>\n                      ) infiltration. CLDN1 knockdown in SZ95 sebocytes recapitulated these findings, inducing a robust pro-inflammatory response (upregulation of IL-1\u03b2, TNF-\u03b1, 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1785747","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T04:23:40Z","timestamp":1780892620000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Differentiation defects reposition sebaceous glands as inflammatory instigators in the early pathogenesis of hidradenitis suppurativa"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibo","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanyan","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangjie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, School of Medicine, Shanghai Jiaotong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos C.","family":"Zouboulis","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Immunology, Universitaetsklinikum Ruppin-Brandenburg, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg","place":["Neuruppin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Renji Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14214","article-title":"What causes hidradenitis suppurativa?-15 years after","volume":"29","author":"Zouboulis","year":"2020","journal-title":"Exp Dermatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.16147","article-title":"Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa","volume":"34","author":"Zouboulis","year":"2020","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s41702-019-0045-z","article-title":"Hidradenitis suppurativa and acne vulgaris and conglobata\u2014systematic review and meta-analysis","volume":"3","author":"Phan","year":"2019","journal-title":"Biomed Dermatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2018.09.040","article-title":"Overall and subgroup prevalence of acne vulgaris among patients with hidradenitis suppurativa","volume":"80","author":"Wertenteil","year":"2019","journal-title":"J Am Acad Dermatol"},{"key":"B5","article-title":"Ala-pdt and blue light therapy for hidradenitis suppurativa","volume":"3","author":"Gold","year":"2004","journal-title":"J Drugs Dermatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.2000.00046.x","article-title":"Topical ala-photodynamic therapy for the treatment of acne vulgaris","volume":"115","author":"Hongcharu","year":"2000","journal-title":"J Invest Dermatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s40257-025-00954-8","article-title":"Is there a place for biologics in acne","volume":"26","author":"Kem\u00e9ny","year":"2025","journal-title":"Am J Clin Dermatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/09546634.2019.1670779","article-title":"Isotretinoin in the treatment of hidradenitis suppurativa: a retrospective study","volume":"32","author":"Patel","year":"2021","journal-title":"J Dermatol Treat"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2023.1187186","article-title":"Case report: Acne vulgaris treatment with 5-aminolaevulinic acid photodynamic therapy and adalimumab: a novel approach","volume":"10","author":"Ping","year":"2023","journal-title":"Front Med (Lausanne)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.pdpdt.2022.103261","article-title":"Clinical practice guidelines for 5-aminolevulinic acid photodynamic therapy for acne vulgaris in China","volume":"41","author":"Wang","year":"2023","journal-title":"Photodiagnosis Photodyn Ther"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.clindermatol.2004.03.004","article-title":"Acne and sebaceous gland function","volume":"22","author":"Zouboulis","year":"2004","journal-title":"Clin Dermatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1029818","article-title":"Sebaceous immunobiology - skin homeostasis, pathophysiology, coordination of innate immunity and inflammatory response and disease associations","volume":"13","author":"Zouboulis","year":"2022","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/j.jaad.2010.09.774","article-title":"Sebaceous gland loss and inflammation in scarring alopecia: a potential role in pathogenesis","volume":"65","author":"Al-Zaid","year":"2011","journal-title":"J Am Acad Dermatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.17981","article-title":"Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis","volume":"181","author":"Clayton","year":"2019","journal-title":"Br J Dermatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2015.08.015","article-title":"Role of sebaceous glands in inflammatory dermatoses","volume":"73","author":"Shi","year":"2015","journal-title":"J Am Acad Dermatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/19381980.2017.1361575","article-title":"Clinical and histopathological characteristics in patients with scarring folliculitis type of acne inversa","volume":"9","author":"Lu","year":"2017","journal-title":"Dermatoendocrinol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2011.10224.x","article-title":"Hidradenitis suppurativa: a disease of the absent sebaceous gland? Sebaceous gland number and volume are significantly reduced in uninvolved hair follicles from patients with hidradenitis suppurativa","volume":"164","author":"Kamp","year":"2011","journal-title":"Br J Dermatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2009.11.017","article-title":"Sebocytes, multifaceted epithelial cells: lipid production and holocrine secretion","volume":"42","author":"Schneider","year":"2010","journal-title":"Int J Biochem Cell Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2009.04.014","article-title":"Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis","volume":"4","author":"Jensen","year":"2009","journal-title":"Cell Stem Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2603","DOI":"10.1016\/j.jid.2021.11.034","article-title":"Aberrant wnt signaling induces comedo-like changes in the murine upper hair follicle","volume":"142","author":"Shang","year":"2022","journal-title":"J Invest Dermatol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1080\/21688370.2020.1848212","article-title":"Cell-cell junctions: structure and regulation in physiology and pathology","volume":"9","author":"Adil","year":"2021","journal-title":"Tissue Barriers"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/s0960-9822(99)80153-5","article-title":"Basement membranes: putting up the barriers","volume":"9","author":"Schwarzbauer","year":"1999","journal-title":"Curr Biology: CB"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.108805","article-title":"Significance of stress keratin expression in normal and diseased epithelia","volume":"27","author":"Cohen","year":"2024","journal-title":"iScience"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15395","article-title":"Tweak mediates inflammation in experimental atopic dermatitis and psoriasis","volume":"8","author":"Sidler","year":"2017","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.1999.00771.x","article-title":"Establishment and characterization of an immortalized human sebaceous gland cell line (Sz95)","volume":"113","author":"Zouboulis","year":"1999","journal-title":"J Invest Dermatol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"68","DOI":"10.4161\/derm.1.2.8472","article-title":"Sebaceous gland lipids","volume":"1","author":"Picardo","year":"2009","journal-title":"Dermatoendocrinol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.19088","article-title":"Lysophosphatidylcholine facilitates the pathogenesis of psoriasis through activating keratinocytes and t cells differentiation via glycolysis","volume":"37","author":"Liu","year":"2023","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"39163","DOI":"10.1038\/s41598-025-24539-x","article-title":"Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea","volume":"15","author":"Yang","year":"2025","journal-title":"Sci Rep"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4161\/derm.1.2.7820","article-title":"Lipid regulation in Sz95 sebocytes by active and inactive phospholipases A2 from Bothrops moojeni venom","volume":"1","author":"Schagen","year":"2009","journal-title":"Dermatoendocrinol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.jid.2025.04.041","article-title":"High-resolution spatial map of the human facial sebaceous gland reveals marker genes and decodes sebocyte differentiation","volume":"146","author":"D\u00fcz","year":"2026","journal-title":"J Invest Dermatol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.12233","article-title":"Preliminary findings suggest hidradenitis suppurativa may be due to defective follicular support","volume":"168","author":"Danby","year":"2013","journal-title":"Br J Dermatol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1016\/j.jid.2024.09.021","article-title":"Apocrine gland damage and the release of specific keratins in early stage indicate the crucial involvement of apocrine glands in hidradenitis suppurativa","volume":"145","author":"Li","year":"2025","journal-title":"J Invest Dermatol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s00424-016-1903-9","article-title":"Tight junctions in skin inflammation","volume":"469","author":"B\u00e4sler","year":"2017","journal-title":"Pflugers Arch"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12041538","article-title":"The role of tight junctions in atopic dermatitis: a systematic review","volume":"12","author":"Katsarou","year":"2023","journal-title":"J Clin Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080973","article-title":"Alteration of tight junction proteins is an early event in psoriasis: putative involvement of proinflammatory cytokines","volume":"175","author":"Kirschner","year":"2009","journal-title":"Am J Pathol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11010127","article-title":"New data on the features of skin barrier in hidradenitis suppurativa","volume":"11","author":"Somogyi","year":"2023","journal-title":"Biomedicines"},{"key":"B37","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.jid.2019.06.150","article-title":"Holocrine secretion occurs outside the tight junction barrier in multicellular glands: lessons from claudin-1-deficient mice","volume":"140","author":"Atsugi","year":"2020","journal-title":"J Invest Dermatol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2007-0651","article-title":"Characterization of bipotential epidermal progenitors derived from human sebaceous gland: contrasting roles of c-myc and beta-catenin","volume":"26","author":"Lo Celso","year":"2008","journal-title":"Stem Cells"},{"key":"B39","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1684\/ejd.2021.3964","article-title":"Formalin-killed propionibacterium acnes activates the aryl hydrocarbon receptor and modifies differentiation of Sz95 sebocytes in vitro","volume":"31","author":"Cao","year":"2021","journal-title":"Eur J Dermatol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1785747\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T04:23:41Z","timestamp":1780892621000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1785747\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,8]]},"references-count":39,"alternative-id":["10.3389\/fimmu.2026.1785747"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1785747","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,8]]},"article-number":"1785747"}}