KIF4A in disease pathogenesis and therapeutics: from molecular mechanisms to clinical translation.

Kinesin family member 4 A (KIF4A) is a multifunctional motor protein essential for chromosome condensation, spindle dynamics, and cytokinesis. Beyond its classical mitotic functions, emerging evidence positions KIF4A as a central regulator of tumorigenesis, therapy resistance, metabolic reprogramming, and immune modulation across diverse cancer types. However, no comprehensive review has integrated its molecular mechanisms with its roles in both oncological and non-oncological diseases, nor clarified its context-dependent behavior, including paradoxical tumor-suppressive effects in cervical cancer. In this review, we synthesize current advances spanning structural biology, transcriptional and post-translational regulation, and pathway-level interactions involving PI3K/AKT, TGF-β/Smad, Hippo-YAP, metabolic remodeling, and DNA damage response networks. We summarize KIF4A's expression and functions across more than 30 malignant tumors and multiple non-neoplastic conditions-including neurodevelopmental disorders, autoimmune diseases, viral infections, fibrotic diseases, and congenital anomalies-highlighting shared molecular themes and disease-specific distinctions. A notable finding is KIF4A's context dependency: while generally oncogenic, high KIF4A expression in cervical cancer correlates with improved survival, suggesting HPV-specific transcriptional rewiring, altered phosphorylation states, or compensatory genome stabilization as potential mechanisms.We further evaluate the translational implications of KIF4A as a biomarker for diagnosis, prognosis, and treatment response, and we critically examine therapeutic strategies targeting KIF4A-ranging from small-molecule inhibitors and gene-silencing approaches to miRNA therapeutics, exosome-based delivery systems, and neoantigen-directed immunotherapy. Finally, we outline major challenges to clinical translation, including its essential roles in mitosis and neuronal integrity, the need for tumor-selective delivery platforms, and incomplete understanding of its tissue-specific functions. Collectively, this review provides a unified mechanistic and translational framework for understanding KIF4A across human diseases, identifies key knowledge gaps, and proposes future research directions to enable safe and effective targeting of this biologically indispensable protein.