Xbp1-KO Mouse

Xbp1, short for X-box binding protein 1, is a transcription factor. It is a key regulator in the unfolded protein response (UPR) pathway, which is activated when endoplasmic reticulum (ER) homeostasis is disrupted. Xbp1's dynamic form is controlled by alternative splicing in response to ER stress, and it is essential for cell fate determination under such stress [4]. Genetic models, like knockout (KO) and conditional knockout (CKO) mouse models, have been crucial in studying its functions.

In non-alcoholic steatohepatitis (NASH), Xbp1 expression was upregulated in patient liver samples. Hepatocyte-specific Xbp1 knockout (Xbp1ΔHep) and macrophage-specific Xbp1 knockout (Xbp1ΔMf) mice fed high-fat or methionine/choline-deficient diets showed inhibited steatohepatitis development compared to wild-type mice. Xbp1-deleted macrophages reduced steatohepatitis by decreasing NLRP3 expression and pro-inflammatory cytokine secretion, and also prevented hepatic stellate cell activation, leading to less fibrosis. Thus, Xbp1 is a potential target for NASH treatment [1]. In colorectal cancer, ablation of Xbp1 in tumor-associated macrophages (TAMs) inhibited the expression of pro-tumor cytokines and enhanced macrophage phagocytosis, suggesting Xbp1 activation in TAMs drives CRC progression and targeting it could be a therapeutic strategy [2]. In MYC-driven breast cancer, Xbp1 was found to be a synthetic lethal partner of MYC. Silencing Xbp1 selectively blocked the growth of MYC-hyperactivated cells, and pharmacological inhibition of IRE1 (which is related to Xbp1 in the UPR) restrained MYC-overexpressing tumor growth in preclinical models [3].

In conclusion, Xbp1 is a vital transcription factor in the UPR pathway, playing a significant role in cell fate determination during ER stress. Studies using KO and CKO mouse models have revealed its importance in diseases such as NASH, colorectal cancer, and MYC-driven breast cancer, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Wang, Qi, Zhou, Haoming, Bu, Qingfa, Wang, Mingming, Lu, Ling. 2022. Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis. In Journal of hepatology, 77, 312-325. doi:10.1016/j.jhep.2022.02.031. https://pubmed.ncbi.nlm.nih.gov/35292349/

2. Zhao, Yahui, Zhang, Weina, Huo, Miaomiao, Xu, Ningzhi, Zhu, Hongxia. 2021. XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer. In Signal transduction and targeted therapy, 6, 357. doi:10.1038/s41392-021-00761-7. https://pubmed.ncbi.nlm.nih.gov/34667145/

3. Zhao, Na, Cao, Jin, Xu, Longyong, Lewis, Michael T, Chen, Xi. 2018. Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. In The Journal of clinical investigation, 128, 1283-1299. doi:10.1172/JCI95873. https://pubmed.ncbi.nlm.nih.gov/29480818/

4. Chen, Shanshan, Chen, Jing, Hua, Xin, Sha, Jun, Zhu, Xiaoli. 2020. The emerging role of XBP1 in cancer. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 127, 110069. doi:10.1016/j.biopha.2020.110069. https://pubmed.ncbi.nlm.nih.gov/32294597/