Actn4, also known as Alpha-actinin-4, is an actin-binding protein belonging to the non-muscle alpha-actinin family. It is crucial for various cellular functions such as cytoskeleton reorganization [1]. It engages in numerous cytoplasmic and nuclear processes, and is involved in signaling pathways like Hippo, Wnt, β-catenin/Slug, and NF-κB [1,2,6,8]. Its biological importance extends to processes like cell proliferation, motility, and epithelial-mesenchymal transition (EMT), making it relevant in understanding normal and disease-related cell behavior [1]. Genetic models, such as Drosophila models, have been used to study Actn4-related podocytopathy, validating the pathogenicity of certain Actn4 mutations [7].

In intrahepatic cholangiocarcinoma (ICC), circActn4 (derived from Actn4 gene) promotes cancer progression by acting as a molecular sponge for miR-424-5p and interacting with YBX1 to activate FZD7 transcription [2]. 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 thymic epithelial tumors, Actn4 is associated with invasion and dissemination via the β-catenin/Slug pathway [6]. In osteosarcoma, Actn4 promotes proliferation, migration, metastasis, and invasion through the NF-κB pathway [8]. Also, Actn4 has been characterized as a novel antiviral target against SARS-CoV-2, with its agonists inhibiting viral infection [4]. In sperm, Actn4 mediates SEPT14 mutation-induced sperm head defects [5].

In conclusion, Actn4 is essential for cytoskeleton-related functions and participates in multiple signaling pathways. Model-based research, including Drosophila models, has revealed its roles in various diseases such as different types of cancers, viral infection, and sperm-related disorders. Understanding Actn4 provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Tentler, Dmitri, Lomert, Ekaterina, Novitskaya, Ksenia, Barlev, Nikolai A. 2019. Role of ACTN4 in Tumorigenesis, Metastasis, and EMT. In Cells, 8, . doi:10.3390/cells8111427. https://pubmed.ncbi.nlm.nih.gov/31766144/

2. Chen, Qinjunjie, Wang, Haibo, Li, Zheng, Wang, Kui, Shen, Feng. 2021. Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription. In Journal of hepatology, 76, 135-147. doi:10.1016/j.jhep.2021.08.027. https://pubmed.ncbi.nlm.nih.gov/34509526/

3. Zhu, Huihui, Liu, Qiuhong, Meng, Qinna, Li, Lanjuan, Ji, Feiyang. 2024. CCT3/ACTN4/TFRC axis protects hepatocellular carcinoma cells from ferroptosis by inhibiting iron endocytosis. In Journal of experimental & clinical cancer research : CR, 43, 245. doi:10.1186/s13046-024-03169-7. https://pubmed.ncbi.nlm.nih.gov/39210442/

4. Zhu, Miao, Huang, Fang, Sun, Huize, Shan, Chao, Guan, Wuxiang. 2024. Characterization of ACTN4 as a novel antiviral target against SARS-CoV-2. In Signal transduction and targeted therapy, 9, 243. doi:10.1038/s41392-024-01956-4. https://pubmed.ncbi.nlm.nih.gov/39289355/

5. Lin, Yu-Hua, Huang, Chia-Yen, Ke, Chih-Chun, Chan, Chying-Chyuan, Lin, Ying-Hung. 2020. ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects. In Biomedicines, 8, . doi:10.3390/biomedicines8110518. https://pubmed.ncbi.nlm.nih.gov/33228246/

6. Nagata, Hideki, Funaki, Soichiro, Kimura, Kenji, Morii, Eiichi, Shintani, Yasushi. 2024. ACTN4 is associated with the malignant potential of thymic epithelial tumors through the β-catenin/Slug pathway. In Cancer science, 115, 3636-3647. doi:10.1111/cas.16313. https://pubmed.ncbi.nlm.nih.gov/39166351/

7. Odenthal, Johanna, Dittrich, Sebastian, Ludwig, Vivian, Habbig, Sandra, Bartram, Malte P. 2022. Modeling of ACTN4-Based Podocytopathy Using Drosophila Nephrocytes. In Kidney international reports, 8, 317-329. doi:10.1016/j.ekir.2022.10.024. https://pubmed.ncbi.nlm.nih.gov/36815115/

8. Huang, Qingshan, Li, Xiaodong, Huang, Zhen, He, Zhizhen, Lin, Jianhua. 2019. ACTN4 Promotes the Proliferation, Migration, Metastasis of Osteosarcoma and Enhances its Invasive Ability through the NF-κB Pathway. In Pathology oncology research : POR, 26, 893-904. doi:10.1007/s12253-019-00637-w. https://pubmed.ncbi.nlm.nih.gov/30879239/