Transforming growth factor alpha promotes bullous pemphigoid pathogenesis by disrupting cell adhesion and inducing inflammation.

Bullous pemphigoid (BP) is a chronic autoimmune blistering disorder characterized by dermal-epidermal separation and immune cell infiltration. The mechanisms underlying epithelial barrier dysfunction in BP remain incompletely understood. Here, we identify transforming growth factor alpha (TGF-α) as a key regulator of BP pathogenesis through disruption of cellular junctions and induction of pro-inflammatory responses. Elevated TGF-α levels in BP lesions correlated with disease severity. Mechanistically, TGF-α downregulated BP180 expression, upregulated matrix metalloproteinases (MMPs), and enhanced chemokine secretion in keratinocytes via epidermal growth factor receptor (EGFR) activation and downstream phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling. Pharmacological inhibition of EGFR and PI3K/Akt pathways mitigated these effects, highlighting their critical roles in disease progression. Additionally, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) signaling was found to amplify TGF-α secretion, further exacerbating inflammatory responses. These findings suggest that TGF-α drives BP pathogenesis by compromising cell adhesion and promoting tissue inflammation. Targeting TGF-α or its downstream effectors may offer novel therapeutic strategies for BP treatment.