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Role of NLRP1 inflammasome in skin cancer and inflammatory skin diseases

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Inflammasomes are cytoplasmic protein complexes that play a crucial role in protecting the host against pathogens by initiating inflammation. Upon activation, these complexes directly regulate the proteolytic processing and activation of proinflammatory cytokines interleukin (IL)-1β and IL-18, inducing a programmed form of cell death called pyroptosis. This exposes intracellular pathogens to immune system surveillance, perpetuating inflammation. Several inflammasome complexes have been identified, with the NLRP1 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-1) inflammasome being the first identified and the main inflammasome sensor protein in human keratinocytes. Specific mutations in NLRP1 or related genes have been associated with rare monogenic skin disorders such as multiple self-healing palmoplantar carcinoma (MSPC). Recent studies have highlighted NLRP1 pathway dysfunction in several seemingly unrelated dermatological conditions. These range from monogenic autoinflammatory diseases to polygenic autoimmune diseases such as vitiligo, psoriasis and atopic dermatitis, as well as several skin cancers, including squamous cell carcinoma, melanoma and Kaposi sarcoma. The aim of this review article is to shed light on pathological dysregulation of the NLRP1 inflammasome in skin diseases and to investigate its potential as a therapeutic target.

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