BHLHE40, a basic helix-loop-helix transcription factor, is emerging as a key regulator in multiple biological processes. It is involved in immune responses, cell differentiation, and is associated with pathways such as hypoxia, endoplasmic reticulum stress, and the mTOR pathway. It plays an important role in various physiological and pathological conditions, including cancer and immune-related diseases. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, have been crucial for studying its functions [5].

In pancreatic ductal adenocarcinoma (PDAC), BHLHE40 is a key regulator in polarizing neutrophils towards a pro-tumour phenotype (TAN-1), which is featured with hyperactivated glycolysis. Immunohistochemistry analysis of PDAC tissues shows that BHLHE40+ neutrophils have an unfavourable prognostic value [1]. In pancreatic cancer cells, BHLHE40 inhibits ferroptosis via upregulating SREBF1 [2]. In metastatic colorectal cancer, it drives the epithelial-mesenchymal transition (EMT), promoting cancer cell proliferation, invasion, migration, and liver metastasis [3]. In an in vitro model of CD8+ T cell exhaustion, BHLHE40 regulates a key differentiation checkpoint between progenitor and intermediate exhausted CD8 T cell subsets [4]. In colon cancer, treatment with a CD40 agonist antibody increases Bhlhe40+ Th1-like cells [6]. In Alzheimer's disease and other lipid-rich tissue disorders, loss or reduction of BHLHE40 in macrophages leads to increased expression of genes involved in cholesterol clearance and lysosomal processing [7]. In Mycobacterium tuberculosis infection, BHLHE40 promotes pro-inflammatory responses in myeloid cells via both IL-10-dependent and-independent mechanisms [8].

In conclusion, BHLHE40 is a crucial transcription factor with diverse functions in immunity, cancer development, and cell-specific responses. Studies using KO/CKO mouse models have significantly advanced our understanding of its roles in diseases such as PDAC, pancreatic cancer, colorectal cancer, Alzheimer's disease, and tuberculosis, providing potential targets for therapeutic intervention.