Myoferlin (MYOF), a member of the ferlin family, is a type II transmembrane protein with a single transmembrane domain at the carbon terminus [2]. It is involved in pivotal physiological functions related to numerous cell membranes, such as extracellular secretion, endocytosis cycle, vesicle trafficking, membrane repair, membrane receptor recycling, and secreted protein efflux [2].

Mutations in the MYOF gene have been identified as a cause of hereditary angioedema with normal C1 esterase inhibitor gene (HAE-nl-C1-INH), previously known as type III HAE [1,3]. In cancer research, MYOF is overexpressed in various cancers like colorectal, pancreatic, breast, melanoma, gastric, and non-small-cell lung cancer, and is associated with high tumor invasion and poor clinical prognosis [2]. Small molecule inhibitors targeting the MYOF-C2D domain can selectively inhibit cancer cell proliferation and migration, indicating its potential as a cancer treatment target [2]. High-throughput screening has led to the discovery of inhibitors like HJ445A that can potently repress gastric cancer cell proliferation and migration [6]. Also, in sepsis, MYOF-enriched monocyte/macrophage subcluster is a favorable prognostic factor [4]. In Trypanosoma cruzi, the orphan myosin MyoF may play a role in endocytosis and along the endocytic pathway [5].

In summary, MYOF is crucial for membrane-related physiological functions. Its dysregulation is linked to diseases such as hereditary angioedema and cancer. Research on MYOF, including through the development of inhibitors, offers potential avenues for treating these diseases. The identification of MYOF's role in different biological contexts, from infectious organisms to human diseases, highlights its significance in understanding disease mechanisms and developing novel therapies.

References:

1. Sinnathamby, Evan S, Issa, Peter P, Roberts, Logan, Shekoohi, Sahar, Kaye, Alan D. 2023. Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology. In Advances in therapy, 40, 814-827. doi:10.1007/s12325-022-02401-0. https://pubmed.ncbi.nlm.nih.gov/36609679/

2. Gu, Haijun, Peng, Yangrui, Chen, Yihua. . An Emerging Therapeutic Approach by Targeting Myoferlin (MYOF) for Malignant Tumors. In Current topics in medicinal chemistry, 20, 1509-1515. doi:10.2174/1568026620666200618123436. https://pubmed.ncbi.nlm.nih.gov/32552653/

3. Santacroce, Rosa, D'Andrea, Giovanna, Maffione, Angela Bruna, Margaglione, Maurizio, d'Apolito, Maria. 2021. The Genetics of Hereditary Angioedema: A Review. In Journal of clinical medicine, 10, . doi:10.3390/jcm10092023. https://pubmed.ncbi.nlm.nih.gov/34065094/

4. Zhang, Yi-Fan, Yi, Zhu-Jun, Zhang, Wen-Feng, Gong, Jian-Ping, Li, Pei-Zhi. 2024. Single-Cell Sequencing Reveals MYOF-Enriched Monocyte/Macrophage Subcluster as a Favorable Prognostic Factor in Sepsis. In Advanced biology, 8, e2300673. doi:10.1002/adbi.202300673. https://pubmed.ncbi.nlm.nih.gov/38456367/

5. Alves, A A, Alcantara, C L, Dantas-Jr, M V A, De Souza, W, Cunha-E-Silva, N L. 2021. Dynamics of the orphan myosin MyoF over Trypanosoma cruzi life cycle and along the endocytic pathway. In Parasitology international, 86, 102444. doi:10.1016/j.parint.2021.102444. https://pubmed.ncbi.nlm.nih.gov/34464754/

6. Gu, Haijun, Zhang, Ting, Guan, Tian, Yi, Zhengfang, Chen, Yihua. 2023. Discovery of a Highly Potent and Selective MYOF Inhibitor with Improved Water Solubility for the Treatment of Gastric Cancer. In Journal of medicinal chemistry, 66, 16917-16938. doi:10.1021/acs.jmedchem.3c01639. https://pubmed.ncbi.nlm.nih.gov/38054798/