Work

Targeting ST18-mediated pathomechanism in pemphigus vulgaris through voltage-dependent anion channel inhibition

Year: 2025

Type: article

Abstract: Background: Pemphigus vulgaris (PV), a severe mucocutaneous blistering disease, results from autoantibody-mediated destabilization of epidermal cell-cell adhesion. A functional risk variant at the ST18 locus was found to promote epidermal ST18 expression. Increased ST18 expression was found to aggravate the deleterious effect of PV autoantibodies in part through induction of p53-mediated proapoptotic pathways. The voltage-dependent anion channel (VDAC) is a key regulator of mitochondria-mediated apoptosis. Objectives: To delineate the interplay between ST18 and VDAC in apoptosis regulation, and the therapeutic potential of VDAC inhibitors in PV. Methods: expression. Immunostaining of skin biopsies was used to evaluate VDAC1 in patients with PV. Apoptotic activity was analysed by caspase 3/7 and TUNEL apoptosis assays, while immunoblotting and a luciferase reporter assay assessed Bcl-2 and p53 pathways. The dispase dissociation assay was used to ascertain the effect VDAC inhibition had on acantholysis. Results: , which encodes the antiapoptotic protein Bcl-2. Of interest, mitochondrial VDAC and p53 antagonize Bcl-2 activity. Patients with PV had dramatically increased epidermal VDAC1 expression. Keratinocytes exposed to AK23, a pathogenic antidesmoglein 3 antibody, and overexpressing ST18, exhibited elevated apoptotic activity. VBIT-12, a VDAC oligomerization inhibitor, robustly attenuated this response and concomitantly led to upregulation of Bcl-2 and to downregulation of p53 transcriptional activity. This suggested that inhibition of VDAC -proapoptotic activity may prevent cell-cell disadhesion in PV. Indeed, VBIT-12 was found to efficiently prevent acantholysis due to PV IgG/AK23. Conclusions: Our findings identify VDAC as a novel factor in the pathogenesis of PV and thus as an innovative and attractive therapeutic target for the treatment of this disease.

Source: Skin Health and Disease

DOI: 10.1093/skinhd/vzaf107