BHLHE40, also known as basic helix-loop-helix transcription factor 40, is a crucial transcription factor. It plays important roles in various biological processes such as immunity, cell differentiation, and metabolism. It is associated with pathways like hypoxia, endoplasmic reticulum stress, and mTOR signaling. BHLHE40 has significant biological importance in understanding diseases, and genetic models like KO/CKO mouse models are valuable for studying its functions [1,2,5].

In pancreatic ductal adenocarcinoma (PDAC), BHLHE40 is a key regulator in polarizing neutrophils towards a pro-tumour phenotype (TAN-1), with TAN-1 featuring hyperactivated glycolysis. Immunohistochemistry analysis of PDAC tissues shows that BHLHE40+ neutrophils have an unfavourable prognostic value [1]. In pancreatic cancer cells, BHLHE40 inhibits ferroptosis by upregulating SREBF1, and an SREBF1 inhibitor suppresses the growth of pancreatic tumours with high BHLHE40 expression [2]. In metastatic colorectal cancer, BHLHE40 promotes the epithelial-mesenchymal transition (EMT), proliferation, invasion, migration, and liver metastasis of cancer cells [3]. In the context of CD8+ T cell exhaustion, BHLHE40 regulates a key differentiation checkpoint between progenitor and intermediate Tex subsets [4]. In colon cancer, treatment with a CD40 agonist antibody increases Bhlhe40+ Th1-like cells and CD8+ memory T cells [6]. In Alzheimer's disease and other disorders of lipid-rich tissues, 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, deletion of Bhlhe40 in lung macrophages and dendritic cells increases mouse susceptibility, and BHLHE40 promotes pro-inflammatory responses in myeloid cells via both IL-10-dependent and-independent mechanisms [8].

In conclusion, BHLHE40 is a key regulator in multiple biological processes and diseases. Studies using KO/CKO mouse models have revealed its role in promoting tumour progression in pancreatic and colorectal cancers, regulating T cell exhaustion, and influencing immune responses in infectious and neurodegenerative diseases. Understanding BHLHE40 provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Wang, Liwen, Liu, Yihao, Dai, Yuting, Chen, Saijuan, Shen, Baiyong. 2022. Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment. In Gut, 72, 958-971. doi:10.1136/gutjnl-2021-326070. https://pubmed.ncbi.nlm.nih.gov/35688610/

2. Cao, Yizhi, Wang, Xuelong, Liu, Yang, Jiang, Lingxi, Shen, Baiyong. 2023. BHLHE40 Inhibits Ferroptosis in Pancreatic Cancer Cells via Upregulating SREBF1. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2306298. doi:10.1002/advs.202306298. https://pubmed.ncbi.nlm.nih.gov/38064101/

3. Yang, Sheng, Zhang, Dongsheng, Sun, Qingyang, Huang, Yuanjian, Sun, Yueming. . Single-Cell and Spatial Transcriptome Profiling Identifies the Transcription Factor BHLHE40 as a Driver of EMT in Metastatic Colorectal Cancer. In Cancer research, 84, 2202-2217. doi:10.1158/0008-5472.CAN-23-3264. https://pubmed.ncbi.nlm.nih.gov/38657117/

4. Wu, Jennifer E, Manne, Sasikanth, Ngiow, Shin Foong, Giles, Josephine R, Wherry, E John. 2023. In vitro modeling of CD8+ T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40. In Science immunology, 8, eade3369. doi:10.1126/sciimmunol.ade3369. https://pubmed.ncbi.nlm.nih.gov/37595022/

5. Cook, Melissa E, Jarjour, Nicholas N, Lin, Chih-Chung, Edelson, Brian T. 2020. Transcription Factor Bhlhe40 in Immunity and Autoimmunity. In Trends in immunology, 41, 1023-1036. doi:10.1016/j.it.2020.09.002. https://pubmed.ncbi.nlm.nih.gov/33039338/

6. Zhang, Lei, Li, Ziyi, Skrzypczynska, Katarzyna M, Zhang, Zemin, Yu, Xin. . Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer. In Cell, 181, 442-459.e29. doi:10.1016/j.cell.2020.03.048. https://pubmed.ncbi.nlm.nih.gov/32302573/

7. Podleśny-Drabiniok, Anna, Novikova, Gloriia, Liu, Yiyuan, Marcora, Edoardo, Goate, Alison Mary. 2024. BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues. In Nature communications, 15, 2058. doi:10.1038/s41467-024-46315-7. https://pubmed.ncbi.nlm.nih.gov/38448474/

8. Hendrix, Skyler V, Mreyoud, Yassin, McNehlan, Michael E, Edelson, Brian T, Stallings, Christina L. . BHLHE40 Regulates Myeloid Cell Polarization through IL-10-Dependent and -Independent Mechanisms. In Journal of immunology (Baltimore, Md. : 1950), 212, 1766-1781. doi:10.4049/jimmunol.2200819. https://pubmed.ncbi.nlm.nih.gov/38683120/