Map3k5, also known as Apoptosis signal-regulating kinase 1 (ASK1), is essential for apoptosis, proliferation, differentiation, and immune responses [4]. It is involved in multiple signaling pathways such as the ASK1/P38 MAPK pathway, ERN1-MAP3K5-p38 pathway, and RIPK1-mediated MAP3K5/JNK and NF-κB pathways, playing a significant role in various biological processes and diseases [1,2,3].

In the context of diarrhea-predominant irritable bowel syndrome (IBS-D), Xingpi Capsule was found to exert antidiarrheal effects by inhibiting the ASK1/P38 MAPK signaling pathway, and hypoxanthine (HPX), a metabolite, was shown to alleviate LPS-induced NCM460 damage by inhibiting Map3k5 and its downstream pathways [1]. In pancreatic ductal adenocarcinoma (PDAC), cetylpyridinium chloride (CPC) induced paraptosis through the activation of the ERN1-MAP3K5-p38 signaling pathway, suppressing pancreatic tumor growth [2]. In D-galactose-induced accelerated aging mice, aerobic exercise down-regulated Map3k5 expression, inhibiting microglia activation and neuroinflammation via modulating the RIPK1-mediated NF-κB and JNK pathways [3].

In conclusion, Map3k5 is crucial in various biological processes and diseases. Research using different models, though not specifically KO/CKO mouse models in these references, has revealed its significance in IBS-D, PDAC, and neuroinflammation. Understanding Map3k5 can potentially provide new insights into the mechanisms of these diseases and offer novel therapeutic strategies.