Actn4, an actin-binding protein, belongs to the family of non-muscle alpha-actinin. It is crucial for multiple cytoplasmic and nuclear processes, such as cytoskeleton reorganization and regulation of signaling pathways [1]. Actn4 has been associated with various biological functions and disease-related pathways, including cancer development, viral infection, and kidney function regulation. Genetic models, like KO or CKO mouse models, can be valuable in further exploring its functions.

In cancer research, Actn4 has been linked to tumorigenesis, metastasis, and epithelial-mesenchymal transition (EMT). In thymic epithelial tumors, overexpression of Actn4 enhanced cell proliferation and invasion, while knockdown suppressed these malignant potential characteristics through the β-catenin/Slug pathway [5]. In hepatocellular carcinoma, the CCT3/Actn4/TFRC axis protects cells from ferroptosis by inhibiting iron endocytosis, and targeting this axis may overcome sorafenib resistance [3]. In intrahepatic cholangiocarcinoma, circular RNA circActn4, originating from the Actn4 gene, promotes tumor progression by acting as a molecular sponge of miR-424-5p and interacting with YBX1 to transcriptionally activate FZD7 [2]. In melanoma, Actn4 stabilizes receptor-interacting protein kinase 1 (RIPK1), forming an oncogenic feed-forward signaling axis of Actn4-RIPK1-NF-κB, and silencing Actn4 suppresses melanoma cell proliferation [8].

In other fields, Actn4 is involved in sperm head formation, as SEPT14 mutations disrupt Actn4 functions and lead to sperm head defects [7]. In kidney podocytes, phosphorylation of Actn4 at serine 159 affects its binding to F-actin, leading to podocyte detachment and proteinuric glomerulosclerosis [6]. Additionally, Actn4 has been characterized as a novel antiviral target against SARS-CoV-2, with its agonists YS-49 and demethyl-coclaurine inhibiting viral infection [4].

In conclusion, Actn4 is essential for a wide range of biological processes. Through model-based research, it has been shown to play significant roles in cancer, sperm development, kidney function, and viral infection. The use of KO/CKO mouse models could potentially further clarify its functions in these specific disease areas and biological processes.