Bhlhe41, also known as DEC2, is a nuclear transcriptional repressor belonging to the basic helix-loop-helix protein superfamily. It is involved in the regulation of numerous physiological processes such as myogenesis, adipogenesis, circadian rhythms, and DNA repair. It also plays roles in cellular functions like regulating mesenchymal stem cell properties, tissue-specific macrophage functions, and lymphoid lineage physiology. In cancer, Bhlhe41 can act as either a tumor suppressor or an oncogene, influencing cell cycle control, apoptosis, invasiveness, epithelial-to-mesenchymal transition, and hypoxia response in the tumor environment [3].

In colorectal cancer, Mettl3-mediated m6A modification promotes Bhlhe41 expression, which in turn activates the CXCL1/CXCR2 axis to enhance myeloid-derived suppressor cell (MDSC) migration, thus inhibiting antitumor immunity. Silencing Mettl3 reduces MDSC accumulation, sustains T-cell activation and proliferation, and suppresses colorectal cancer growth in multiple mouse models [1]. In the infarcted myocardium, a transient appearance of monocyte-derived Bhlhe41+ macrophages at day 7 post-myocardial infarction (MI) contributes to suppressing myofibroblast activation, preventing excessive fibrosis, and limiting the expansion of the developing infarct area [2].

In summary, Bhlhe41 is crucial in both physiological processes and disease conditions. Gene knockout studies in mice have revealed its diverse functions, such as in the regulation of immune cell-mediated tumor suppression in colorectal cancer and myocardial remodeling post-MI. Understanding Bhlhe41 through these model-based researches provides insights into disease mechanisms and potential therapeutic targets.