Heat shock protein 90 Inhibition: A potential double- or triple-edged sword in the treatment of mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is a subtype of autoimmune subepidermal blistering diseases characterized by autoantibodies to structural components of the hemidesmosome primarily affecting mucous membranes. Inflammation-related progressive scarring can lead to serious complications, including blindness, and the disease may be associated with malignancy. Conventional immunosuppressive treatment is often insufficiently effective and limited due to side effects, warranting new therapeutic options ideally targeting both inflammation and extensively recalcitrant cicatrization. Heat shock protein 90 (Hsp90) is a cell stress-inducible chaperone required for the function of a large number of client proteins, and its pharmacological inhibition has proven to be effective and relatively safe in patients with cancer. Recent observations also suggest a promising role of Hsp90 as drug target in preclinical in vivo murine models of autoimmune diseases such as subepidermal bullous and fibrotic autoimmune disorders comprising epidermolysis bullosa acquisita and systemic sclerosis, respectively, which exhibit some pathophysiological features reminiscent of MMP. This article thus hypothesizes that Hsp90 blockade could represent a double-edged sword in MMP treatment by targeting pathogenic factors of inflammatory blister and fibrosis formation. Moreover, Hsp90 inhibitors could even be proclaimed as a triple-edged sword in case of an underlying malignancy. Future studies investigating the role of Hsp90 in MMP are needed to clarify whether Hsp90 inhibition could become a novel treatment approach for patients with this potentially devastating disease.