Role of ACTN4 in cancer development and targeting ACTN4 in cancer therapy

ACTN4 (α-actinin-4), a member of the α-actinin family, is a key regulator of cytoskeletal organization and cell motility through actin filament cross-linking. Accumulating evidence indicates that ACTN4 contributes to cancer initiation and progression through multiple mechanisms, positioning it as a promising target for oncological research. ACTN4 amplification, mutation, and overexpression are associated with tumorigenesis, metastasis, and poor prognosis across multiple cancer types, although causal relationships vary by context. This review provides a systematic overview of the structural and functional characteristics of ACTN4, its role as an oncogene, and its molecular interactions and binding partners. It further explores the hallmarks of ACTN4 in cancer, including effects on tumor cell survival, proliferation, angiogenesis, metastasis, cell cycle regulation, and immune response. The review also discusses small-molecule compounds and natural products that modulate ACTN4 activity, along with emerging strategies such as targeted protein degradation, synthetic lethality, and indirect targeting, accompanied by a critical assessment of challenges in therapeutically targeting this ubiquitously expressed cytoskeletal protein. Additionally, we evaluate ACTN4 as a biomarker and discuss requirements for assay standardization, clinical validation, and patient stratification. This review aims to provide a comprehensive account of current advances in ACTN4 research, offering insights into personalized diagnosis and molecular targeted therapy for cancer.