Multifaceted roles of KCTD17 in cellular homeostasis and disease.

Potassium channel tetramerization domain-containing protein 17 (KCTD17) is part of the BTB/POZ domain-containing KCTD protein family and serves as a multifunctional regulator of cellular homeostasis. As an adaptor protein associated with Cullin 3 (CUL3)-based E3 ubiquitin ligase complexes, KCTD17 plays a critical role in selective protein ubiquitination and proteasomal degradation, influencing the stability of various cellular proteins. This function links KCTD17 to numerous biological processes, including organelle dynamics, cell differentiation, intracellular signaling, metabolic regulation, stress responses, tissue remodeling, and disease progression. Notably, the effects of KCTD17 are highly context-dependent, varying with cell type, substrate availability, and pathological conditions. While recent studies have begun to uncover several pathways associated with KCTD17, its complete range of substrates, regulatory mechanisms, and physiological significance are still not fully understood. In this review, we summarize the current understanding of KCTD17's molecular functions and biological mechanisms, emphasizing its role as a proteostatic regulator. We also explore its potential relevance to human diseases and highlight key unresolved questions, such as substrate specificity, tissue-dependent functions, functional redundancy with related KCTD proteins, and therapeutic potential. Gaining a deeper understanding of KCTD17-dependent protein regulation may offer new insights into proteostasismediated cellular regulation and disease mechanisms.