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 (GS) mutations, particularly in the Nicastrin (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 (UPFs). 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 (EDCs), 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 GS-related diseases. RNAseq profiling of scRNA and siNCSTN fibroblasts and keratinocytes. Also included: Gamma secreatase inhibitor treated fibroblasts and pED treated fibroblasts.