Tmem9b, a single-span type I transmembrane protein, has multiple functions. It is an important regulator in several biological pathways. It strongly interacts with neuronal endosomal ClC-3 and ClC-4 transporters, regulating their activities, which is crucial for neuronal endosomal homeostasis [1,3,6]. It also participates in inflammatory signaling pathways, being required for the production of proinflammatory cytokines induced by TNF, IL-1β, and TLR ligands, acting downstream of RIP1 and upstream of the MAPK and IkappaB kinases at the level of the TAK1 complex [5].

Mice lacking both TMEM9 and TMEM9B (β -subunits for endosomal ClC-3, ClC-4, and ClC-5) displayed severely reduced levels of all three CLCs and died embryonically or shortly after birth, highlighting its importance in endosomal ion homeostasis [3]. In breast cancer, lncRNA MIR4435-2HG promotes tumor-related processes like proliferation, migration, invasion, and epithelial-mesenchymal transition via targeting miR-22-3p/TMEM9B axis [2]. In osteosarcoma, the expression of TMEM9B was lower in the high-risk group and was positively associated with the overall survival of patients, suggesting it might be a potential therapeutic target [4].

In conclusion, Tmem9b is essential for endosomal ion transport regulation, inflammatory signaling, and is involved in diseases such as breast cancer and osteosarcoma. Mouse models lacking relevant β-subunits have revealed its significance in endosomal function and embryonic survival, providing insights into disease mechanisms and potential therapeutic targets.