Tmem9, or Transmembrane protein 9, is a transmembrane protein involved in multiple biological functions. It is associated with pathways like autophagy, Wnt/β -catenin, and MEK/ERK/STAT3, and is crucial for processes such as vesicle acidification, lysosomal protein degradation, and autophagy regulation [1,2,3]. Genetic models, including KO/CKO mouse models, are valuable for studying its functions.

In KO mouse models, Tmem9 knockout impairs hepatic regeneration, as it aberrantly increases adenomatosis polyposis coli (Apc) and reduces Wnt signaling. Mechanistically, Tmem9 down -regulates APC through lysosomal protein degradation via v -ATPase [2]. Genetic ablation of Tmem9 also inhibits colorectal cancer cell proliferation in vitro, ex vivo, and in vivo mouse models [3]. In the context of Alzheimer's disease, physical exercise down -regulates microglial Tmem9 protein, inhibits C1q activation, and decreases C1q -dependent microglial synapse engulfment, eventually ameliorating cognitive impairment in 5xFAD mice [4].

In conclusion, Tmem9 plays essential roles in processes such as liver regeneration, tumorigenesis, and alternative autophagy. The study of Tmem9 KO/CKO mouse models has significantly contributed to understanding its functions in diseases like hepatocellular carcinoma, colorectal cancer, and Alzheimer's disease, providing potential therapeutic targets for these conditions.