Aquaporins as Regulators of Cutaneous Malignancies: A Comprehensive Review

Highlights: What are the main findings? Specific aquaporin isoforms show a layer-dependent expression in the skin and regulate hydration, cellular proliferation, inflammatory responses, and tissue homeostasis. Altered aquaporin expression and activity are linked to skin cancer development and progression, contributing to tumor growth, invasion, and aggressiveness in both non-melanoma skin cancers and malignant melanoma. What are the implications of the main findings? Aquaporins act as key regulators of skin cancer biology, shaping tumor growth, invasion, and adaptation to microenvironmental stress. Defining isoform-specific aquaporin functions may facilitate the identification of novel therapeutic targets and guide future research in cutaneous oncology. Aquaporins (AQPs) are a family of small integral membrane proteins that mediate the selective transport of water and, in some cases, small solutes such as glycerol and hydrogen peroxide. In the skin, distinct AQP isoforms are expressed throughout the epidermis, dermis, and hypodermis, where they play key roles in maintaining hydration, regulating keratinocyte and fibroblast proliferation, modulating inflammatory responses, and preserving overall tissue integrity. Increasing evidence indicates that aberrant AQP expression or function contributes to skin carcinogenesis, influencing tumor initiation, local invasion, metastasis, and responses to microenvironmental stress. Alterations in specific AQP isoforms have been associated with both major classes of cutaneous malignancies—non-melanoma skin cancers (NMSC), including basal cell carcinoma and squamous cell carcinoma, as well as malignant melanoma (MM)—yet their mechanistic contributions remain incompletely understood. This review synthesizes current knowledge on the involvement of each AQP isoform in skin cancer pathogenesis and progression, integrating findings from molecular, cellular, and in vivo studies. By clarifying the diverse roles of AQPs in cutaneous malignancies, this work aims to support the development of targeted interventions and guide future research in this rapidly evolving field.