TMEM147, a transmembrane protein, localizes at the endoplasmic reticulum and nuclear envelope. It is involved in regulating cholesterol homeostasis, as it interacts with key enzymes like 7-dehydrocholesterol reductase (DHCR7) and lamin B receptor (LBR) [6]. This interaction affects cellular cholesterol levels, cholesteryl ester levels and profile, and cellular cholesterol uptake, suggesting its importance in lipid-related biological processes. It may also be involved in biogenesis of multi-pass membrane proteins and has been associated with neurodevelopment [10].

In hepatocellular carcinoma (HCC), TMEM147 is upregulated and promotes tumor cell proliferation, metastases, ferroptosis resistance, and M2 macrophage polarization. It interacts with DHCR7, affecting cholesterol homeostasis and increasing extracellular 27-hydroxycholesterol (27HC) levels. 27HC upregulates glutathione peroxidase 4, leading to ferroptosis resistance and HCC proliferation. HCC cell-derived 27HC also activates M2 macrophage polarization, promoting HCC cell invasion and migration [1]. High TMEM147 expression in HCC is related to poor prognosis, and it can serve as a diagnostic biomarker with higher efficacy than AFP [2]. In addition, it is associated with immune cell infiltration in HCC, such as Th2 cells, follicular helper T cells, macrophages, and NK CD56 bright cells [3]. Pan-cancer analysis shows differential TMEM147 expression across various cancers, and high expression is associated with poor disease-specific survival, overall survival, and progression-free interval, suggesting its potential as a prognostic biomarker [5].

In epithelial ovarian cancer, the feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 drives lipophagy to induce cisplatin resistance [4]. In gastric cancer, lncRNA TMEM147-AS1 acts as a miR-326 sponge to upregulate SMAD5, aggravating malignancy [7]. In prostatic carcinoma, TMEM147-AS1 promotes invasion and proliferation via the miR-133b/ZNF587 axis, regulating the Warburg effect [8].

Biallelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly due to ER-translocon and nuclear organization dysfunction [10]. A novel loss-of-function variant in TMEM147 also causes intellectual disability and spasticity [9].

In conclusion, TMEM147 plays crucial roles in multiple biological processes and diseases. In cancer, it often promotes tumor progression, and in neurodevelopmental disorders, loss-of-function variants lead to intellectual disability. Functional studies, especially those using loss-of-function models, have revealed its importance in cholesterol homeostasis, immune regulation, and cell proliferation, providing potential therapeutic targets for related diseases.