TMEM164, the transmembrane protein 164, has emerged as a key player in multiple biological processes. It is notably involved in autophagy-related pathways, specifically in the context of ferroptosis, an iron-dependent form of regulated cell death. It also has potential implications in neurodegenerative disorders, making it of significant biological importance. Genetic models, such as KO/CKO mouse models, are valuable tools for studying its functions [1,2].

In terms of core findings, genetic ablation of TMEM164 in ferroptosis-sensitive cancer cell lines led to selective reductions in C20:4 ether phospholipids (ePLs), which protected cells from ferroptosis [3]. In LUAD, TMEM164 expression is downregulated, and increasing its expression promotes ATG5-dependent autophagosome formation, facilitating ferroptosis and inhibiting tumor progression [4]. In non-small cell lung cancer (NSCLC), TMEM164 overexpression inhibits invasion, migration, and cell proliferation by promoting autophagy-mediated ferroptosis, and co-administration with anti-PD-1 antibodies shows synergistic anti-tumor effects [5]. In mouse models of neurodegenerative disorders, astrocyte-specific overexpression of TMEM164 inhibits the induction of neurotoxic reactive astrocytes, preventing neuronal loss and motor deficits in a Parkinson's disease model and amyloid β deposition, neurodegeneration, and memory decline in the 5XFAD Alzheimer's disease mouse model [2].

In conclusion, TMEM164 plays a crucial role in autophagy-dependent ferroptosis, which is relevant to cancer treatment. Its functions in modulating autophagy and ferroptosis are revealed through gene-knockout mouse models, offering potential therapeutic targets for cancer and neurodegenerative disorders. These model-based studies enhance our understanding of its role in disease-related biological processes [1,2,3,4,5].

References:

1. Liu, Jiao, Liu, Yang, Wang, Yuan, Kang, Rui, Tang, Daolin. 2022. TMEM164 is a new determinant of autophagy-dependent ferroptosis. In Autophagy, 19, 945-956. doi:10.1080/15548627.2022.2111635. https://pubmed.ncbi.nlm.nih.gov/35947500/

2. Zhang, Liansheng, Jia, Zhiheng, Wu, Qiang, Xu, Zhengzheng, Zhou, Haibo. 2023. Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice. In Nature metabolism, 5, 1787-1802. doi:10.1038/s42255-023-00887-8. https://pubmed.ncbi.nlm.nih.gov/37679556/

3. Reed, Alex, Ware, Timothy, Li, Haoxin, Fernando Bazan, J, Cravatt, Benjamin F. 2023. TMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids. In Nature chemical biology, 19, 378-388. doi:10.1038/s41589-022-01253-7. https://pubmed.ncbi.nlm.nih.gov/36782012/

4. Su, Yongxiang, Li, Lintao, Chen, Junhai, Gao, Chao. 2024. TMEM164 promotes ferroptosis by selectively mediating ATG5-dependent autophagosome formation to inhibit the progression of LUAD. In Autoimmunity, 57, 2410192. doi:10.1080/08916934.2024.2410192. https://pubmed.ncbi.nlm.nih.gov/39392409/

5. ALMatrafi, Tahani Ahmad. 2025. Deciphering the role of TMEM164 in autophagy-mediated ferroptosis and immune modulation in non-small cell lung cancer. In Cellular immunology, 409-410, 104915. doi:10.1016/j.cellimm.2024.104915. https://pubmed.ncbi.nlm.nih.gov/39798196/