Map3k5, also known as apoptosis signal-regulating kinase 1 (ASK1), is a crucial mitogen-activated protein kinase kinase kinase. It is essential for apoptosis, proliferation, differentiation, and immune responses [4]. Map3k5 is involved in multiple signaling pathways such as ASK1/P38 MAPK, ERN1-MAP3K5-p38, and RIPK1-mediated MAP3K5/JNK and NF-κB pathways, playing a significant role in various biological processes and disease conditions [1,2,3]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In an in vivo experiment on pancreatic ductal adenocarcinoma (PDAC), cetylpyridinium chloride (CPC) was found to trigger paraptosis and suppress pancreatic tumor growth via the ERN1-MAP3K5-p38 pathway [2]. In D-galactose-induced accelerated aging mice, aerobic exercise decreased Map3k5 expression in the hippocampus, which was associated with the suppression of microglia activation and neuroinflammation through modulating RIPK1-mediated MAP3K5/JNK and NF-κB pathways [3]. In a study on diarrhea-predominant irritable bowel syndrome (IBS-D), in vitro experiments demonstrated that hypoxanthine (HPX) alleviated LPS-induced NCM460 damage by inhibiting Map3k5 and its downstream pathways [1].

In conclusion, Map3k5 is vital for multiple biological functions, with its dysregulation contributing to various diseases like PDAC, IBS-D, and neurodegenerative-related conditions involving microglia activation. Studies using mouse models have significantly enhanced our understanding of Map3k5's role in these disease areas, providing insights for potential therapeutic strategies.

References:

1. Qian, Weina, Li, Weili, Chen, Xiaoyang, Wang, Yong, Wang, Wei. 2023. Exploring the mechanism of Xingpi Capsule in diarrhea predominant-irritable bowel syndrome treatment based on multiomics technology. In Phytomedicine : international journal of phytotherapy and phytopharmacology, 111, 154653. doi:10.1016/j.phymed.2023.154653. https://pubmed.ncbi.nlm.nih.gov/36641976/

2. Tang, Hu, Chen, Fangquan, Gao, Wanli, Tang, Daolin, Liu, Jiao. 2024. Cetylpyridinium chloride triggers paraptosis to suppress pancreatic tumor growth via the ERN1-MAP3K5-p38 pathway. In iScience, 27, 110598. doi:10.1016/j.isci.2024.110598. https://pubmed.ncbi.nlm.nih.gov/39211547/

3. Liu, Yang, Meng, Xiaokang, Tang, Changfa, Tao, Kun, Guo, Wen. 2024. Aerobic exercise modulates RIPK1-mediated MAP3K5/JNK and NF-κB pathways to suppress microglia activation and neuroinflammation in the hippocampus of D-gal-induced accelerated aging mice. In Physiology & behavior, 286, 114676. doi:10.1016/j.physbeh.2024.114676. https://pubmed.ncbi.nlm.nih.gov/39181380/

4. Pu, L, Zhang, L C, Zhang, J S, Wu, Q Q, Wang, L X. 2016. Porcine MAP3K5 analysis: molecular cloning, characterization, tissue expression pattern, and copy number variations associated with residual feed intake. In Genetics and molecular research : GMR, 15, . doi:10.4238/gmr.15037998. https://pubmed.ncbi.nlm.nih.gov/27525933/