Them4, also known as carboxyl‑terminal modulator protein 1 (CTMP1), is a member of the thioesterase superfamily and has acyl-CoA thioesterase activity [4,7]. It is an Akt kinase-binding protein, playing a role in the Akt pathway which regulates growth, proliferation, and metabolism of tumor cells and stem cells, thus influencing the development and treatment of various diseases [1].

Some studies initially regarded Them4 as an endogenous inhibitor of Akt, suppressing Akt phosphorylation in diseases like lung, pancreatic, and liver cancers [1]. However, it was later found to promote tumor cell proliferation in breast and nasopharyngeal carcinomas by positively regulating Akt activity [1]. In cholangiocarcinoma, CARD9 promotes cancer progression by interacting with Them4, facilitating AKT and mTOR phosphorylation [2]. In colon cancer, exosomal miR-183-5p shuttled by M2-polarized tumor-associated macrophages targets Them4, mediating the Akt/NF-κB pathway to accelerate cancer progression [3]. Also, in glioma, ENOPH1 activates the PI3K/AKT/mTOR signaling pathway by regulating Them4, promoting glioma cell proliferation and migration [5]. In macrophages, vitamin D suppresses the Akt/NF-κB/COX-2 pathway by up-regulating Them4, restraining macrophage-mediated inflammatory processes [6].

In conclusion, Them4 is a key regulator in the Akt pathway with complex and context-dependent functions. Its role in promoting or inhibiting tumor cell proliferation in different cancers, as well as its involvement in inflammatory regulation, highlights its importance in understanding disease mechanisms. The study of Them4 through various models helps in unravelling the molecular basis of these diseases, potentially providing new therapeutic targets.