Functional roles of Keratin 6A in disease pathogenesis across cancer and skin disorders.

Keratin 6A (KRT6A) is an epithelial-specific type II keratin localized within cytoskeletal intermediate filaments and functions in cooperation with KRT16/17 to maintain epidermal homeostasis and tissue repair. Accumulating evidence highlights its multifaceted roles in cancer. Aberrant KRT6A expression promotes cell cycle progression, epithelial-mesenchymal transition, migration, and invasion, thereby driving tumor initiation and metastasis, although tumor-suppressive effects have been observed in specific contexts. Mechanistically, KRT6A regulates adhesion, cytoskeletal remodeling, and critical signaling pathways, thereby reshaping tumor immunity and metabolism to facilitate immune evasion and metabolic dysregulation. Elevated KRT6A expression is strongly associated with resistance to chemotherapy, targeted therapy, and radiotherapy. Therapeutic approaches targeting KRT6A include nucleic acid-based interventions, protein degradation strategies, inhibition of upstream regulatory pathways, and combinatorial regimens to overcome drug resistance. Clinically, KRT6A has emerged as both a diagnostic and prognostic biomarker, supporting treatment monitoring and enhancing predictive models for risk stratification and individualized outcome evaluation. Beyond oncology, mutations in KRT6A underlie pachyonychia congenita, and its dysregulation contributes to epidermal hyperproliferative disorders such as psoriasis. Overall, systematic elucidation of the structure-function-pathway-clinical axis of KRT6A offers new opportunities for precision medicine and supports its potential as a therapeutic target in cancer management.