MAP3K2 (mitogen-activated protein kinase kinase kinase 2) is a serine/threonine protein kinase that functions as a key component of MAPK signaling cascades, particularly regulating ERK and JNK pathways 12. The protein serves as a critical upstream activator that phosphorylates downstream MAP kinases, influencing cell proliferation, apoptosis, and inflammatory responses 13. MAP3K2 is subject to post-translational regulation through methylation by SMYD3, which enhances MAPK signaling activation and promotes oncogenic Ras/ERK pathway activity 45. In cancer contexts, MAP3K2 is frequently overexpressed and associated with tumor progression, metastasis, and poor prognosis across multiple cancer types including lung adenocarcinoma, prostate cancer, and hepatocellular carcinoma 142. The gene is also regulated by multiple microRNAs including miR-338-3p, miR-181a, miR-1184, miR-761, and miR-302a, which typically act as tumor suppressors by targeting MAP3K2 to inhibit cancer cell proliferation and invasion 16372. In cardiovascular disease, MAP3K2 contributes to hypoxia-induced cardiomyocyte injury, inflammation, and oxidative stress 37.