Tm6sf2, or Transmembrane 6 superfamily 2, is a gene located at the locus 19p12. It has been recognized to play a crucial role in regulating plasma lipids, being involved in pathways related to intestinal cholesterol absorption, hepatic cholesterol biosynthesis and transport [1]. Genetic studies indicate its significance in cardiometabolic diseases, especially non-alcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD) [2,4]. Animal models, like mice with Tm6sf2 manipulation, have been instrumental in validating its function in vivo [1].

In gene-knockout studies, myeloid cell-specific Tm6sf2 knockout (LysM Cre+/Tm6sf2fl/fl/ApoE-/-, TM6 mKO) mice fed a Western diet showed inhibited atherosclerosis and decreased foam cells in plaques without changing plasma lipid profiles. RNA-sequencing of their bone marrow-derived macrophages (BMDMs) demonstrated down-regulation of genes related to inflammation, cholesterol uptake, and endoplasmic reticulum (ER) stress [4]. Hepatocyte-specific Tm6sf2 knockout (Tm6sf2 ∆hep) mice fed high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet had exacerbated tumour formation in metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma (MASLD-HCC), along with reduced interferon-gamma (IFN-γ)+CD8+ T cells in tumours [3]. Intestinal epithelial cell-specific knockout of Tm6sf2 (Tm6sf2ΔIEC) in mice led to the development of metabolic dysfunction-associated steatohepatitis (MASH), accompanied by impaired intestinal barrier and microbial dysbiosis [5].

In conclusion, Tm6sf2 is a key regulator of plasma lipid levels and has a protective role against MASLD. Its deficiency in specific cell types in mouse models reveals its role in promoting antitumour immunity, inhibiting atherosclerosis, and protecting against MASH. These model-based studies highlight Tm6sf2's potential as a therapeutic target in cardiometabolic diseases, such as NAFLD, ASCVD, and MASLD-HCC [1,3,4,5].