Plastic associated endocrine disruptors reduce Nicastrin protein and potentiate inflammation in hidradenitis suppurativa skin disease
Hidradenitis Suppurativa (HS) is an inflammatory skin disorder with limited treatments and unclear etiology. While monogenic HS is linked to gamma secretase mutations, particularly in the NCSTN subunit, the pathogenesis of the more common sporadic form remains uncertain, though associated with risk factors such as diets high in ultra-processed foods. Consistent with the clinical overlap between sporadic and monogenic HS, we find loss of NCSTN protein in sporadic HS fibroblasts. We hypothesize the rising incidence of sporadic HS and its hormonal associations implicate endocrine-disrupting chemicals, especially plastic-associated EDCs (p-EDs) common in UPFs. We detect elevated p-ED adducts in HS skin, persisting in ex vivo cultured fibroblasts. At nanomolar concentrations, p-EDs inhibits NCSTN and primes fibroblasts for inflammation, mimicking NCSTN knockdown. These findings suggest p-ED exposure contributes to HS pathogenesis, highlighting the need to address environmental exposures in HS and other gamma secretase-related diseases.
Authors
- Kaitlin L. Williams (ORCID: https://orcid.org/0000-0002-8768-0488)
- Nathan K. Archer (ORCID: https://orcid.org/0000-0002-8212-8985)
- Yingchao Xue (ORCID: https://orcid.org/0000-0002-7830-3146)
- Carrie A. Cox
- Amy van Ee (ORCID: https://orcid.org/0000-0002-1277-3137)
- Luis A. Garza (ORCID: https://orcid.org/0000-0002-6547-9695)
- J.P. Reilly (ORCID: https://orcid.org/0000-0002-4109-1186)
- Kurunthachalam Kannan (ORCID: https://orcid.org/0000-0002-1926-7456)
- Beita Badiei (ORCID: https://orcid.org/0009-0009-4183-9383)
- E. G. Martinez Peña (ORCID: https://orcid.org/0000-0003-4545-7154)
- Sewon Kang (ORCID: https://orcid.org/0000-0002-7841-9392)
- Julie Caffrey (ORCID: https://orcid.org/0000-0001-5782-3532)
- Charles Kirby (ORCID: https://orcid.org/0000-0001-7756-2114)
- Maureen A. Kane (ORCID: https://orcid.org/0000-0002-5525-9170)
- A. Willis (ORCID: https://orcid.org/0000-0002-1812-5085)
- William Andrews (ORCID: https://orcid.org/0000-0003-4780-8835)
- Hana Minsky (ORCID: https://orcid.org/0000-0001-8038-4646)
- Ang Li (ORCID: https://orcid.org/0000-0002-6816-7064)
- Sam Lee (ORCID: https://orcid.org/0000-0003-3760-8960)
- Nina Rossa Haddad (ORCID: https://orcid.org/0009-0000-1132-6637)
- M. Sun
- S. Rajagopalan (ORCID: https://orcid.org/0000-0003-4096-9740)
- Alan Johnson (ORCID: https://orcid.org/0009-0006-3869-8581)
- Leigh Curvin-Aquilla
Institutions
- University of Maryland, Baltimore (US)
- New York State Department of Health (US)
- Wadsworth Center (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-65789-7
- Primary Topic
- Hidradenitis Suppurativa and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Johns Hopkins University
- Maryland Stem Cell Research Fund
- National Institutes of Health