Map3k3, also known as Mitogen-activated protein kinase kinase kinase 3, is ubiquitously expressed in numerous tissues. It is activated by various extracellular stimuli and plays a role in regulating processes such as cell proliferation and differentiation. It is involved in multiple signaling pathways including NF-κB, ERK1/2, JNK, p38, and the apoptosis pathway [3,5]. Understanding its function is crucial as it has implications in several biological processes and disease conditions. Genetic models, especially mouse models, have been valuable in studying Map3k3.

In the context of cerebral cavernous malformations (CCMs), a somatic gain-of-function mutation in Map3k3 (p.I441M) has been identified in about 40% of patients with sporadic CCMs [1,2]. Mouse models with endothelial-specific expression of Map3k3I441M have been developed. These models develop CCM-like lesions, with the mutant promoting endothelial apoptosis in juvenile mice [2]. The activation of the PI3K pathway counteracts apoptosis and facilitates lesion progression. Moreover, treatment with rapamycin, an mTOR inhibitor, can alleviate CCM lesions in these mouse models [1,2]. In simplex CCMs, patients with Map3k3 mutation have a lower risk of hemorrhage events compared to those with CCM gene mutations [4]. In ovarian carcinoma, overexpression of Map3k3 promotes tumor growth through activation of the NF-κB signalling pathway, and is associated with poor survival [3,5]. Also, miR-181b targets Map3k3 to regulate vascular endothelial aging by modulating a MAP3K3/MKK/MAPK signaling pathway [6].

In conclusion, Map3k3 is a key regulator in multiple biological processes. Through model-based research, especially KO/CKO mouse models, it has been revealed to play a significant role in CCMs, ovarian carcinoma, and vascular endothelial aging. The findings from these models help in understanding the underlying mechanisms of these diseases and potentially developing new therapeutic strategies.