Forkhead box K1 (FOXK1) is an important member of the FOX transcription factor family and functions as a signal-responsive regulator of cellular metabolism, proliferation, differentiation, and stress adaptation. FOXK1 activity is tightly controlled by a multilayered regulatory network, including genetic and epigenetic alterations, transcriptional regulation, non-coding RNAs, and diverse post-translational modifications. These regulatory networks collectively coordinate FOXK1 stability, subcellular localization, and transcriptional activity in a context-dependent manner. Disruption of this tightly balanced regulatory system can lead to sustained FOXK1 activation and contribute to disease pathogenesis.In cancer, FOXK1 predominantly functions as an oncogenic transcription factor that promotes metabolic reprogramming, maintenance of cancer stem cell properties, epithelial-mesenchymal transition, invasion, metastasis, vasculogenic mimicry, and therapeutic resistance. Beyond oncology, emerging evidence further implicates FOXK1 in metabolic disorders, inflammatory diseases, reproductive dysfunction, and neurological conditions, suggesting broader context-dependent pathological functions. Given its central role in multiple disease-associated signaling networks, FOXK1 has emerged as a potential therapeutic target. In this review, we systematically summarize the structural characteristics and regulatory mechanisms of FOXK1, and comprehensively discuss its roles in physiological and pathological processes. We further highlight current advances in FOXK1-targeted therapeutic strategies and address the key challenges for clinical translation. This review provides a conceptual framework for future therapeutic strategies and rational drug development targeting FOXK1.
He et al. (Wed,) studied this question.