The Dickkopf Protein Family in Non-Neoplastic Disorders: Emerging Roles and Therapeutic Targeting.

The Dickkopf (DKK) family of secreted glycoproteins, comprising DKK1-4, serves as a pivotal regulator of the Wnt signaling pathway. Acting as canonical antagonists of the Wnt/β-catenin cascade, these proteins are indispensable for essential biological processes such as cellular proliferation, differentiation, development, and tissue homeostasis. In recent years, aberrant expressions of DKK proteins has been extensively documented in multiple cancers. Simultaneously, their pathophysiological roles and clinical relevance in non-oncological diseases have garnered growing attention. Disorders such as osteoporosis and arthritis, chronic kidney disease (CKD), myocardial injury, as well as neurodegenerative and dermatological conditions, including Alzheimer's disease (AD) and alopecia, have all been linked to DKK family members. These broad associations emphasize their substantial potential as diagnostic biomarkers and as promising therapeutic targets. This review provides a systematic synthesis of recent research within the past three years on the roles of the DKK protein family in diverse non-oncological diseases, further examining their prospective applications as biomarkers and therapeutic targets while addressing related challenges, with the aim of offering novel insights into diagnosis and treatment.