Smyd2, or SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2, is a protein lysine methyltransferase. It methylates histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) and diverse non-histone proteins. Its activity is crucial for normal organismal development and regulating various pathophysiological processes, such as those related to cardiovascular disease and cancer [3].

In PH (pulmonary hypertension) studies, LLY-507-mediated targeted inhibition of Smyd2 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in rats, while Smyd2-vTg mice showed more severe PH phenotypes after chronic hypoxia treatment. Mechanistically, Smyd2 monomethylates non-histone PPARγ, inhibiting its nuclear translocation and activation, thus accelerating PASMC proliferation and PH through mitophagy [1].

In cancer research, knockdown of Smyd2 or treatment with its inhibitor AZ505 led to persistent DNA damage and improper nonhomologous end-joining repair in tumor cells, activating the cGAS-STING pathway and antitumor immunity [2].

In vascular smooth muscle cell (VSMC) research, SMC-specific knockout of Smyd2 exacerbated neointima formation after vascular injury in mice, while Smyd2 overexpression inhibited VSMC proliferation and migration in vitro and arterial narrowing in injured vessels in mice. Smyd2 regulated VSMC contractile gene expression and phenotypic switching through interaction with myocardin [4]. Also, in the context of neointimal hyperplasia, treatment with Smyd2 inhibitor LLY-507 or Smyd2 knockdown significantly inhibited VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice [5].

In conclusion, Smyd2 plays essential roles in multiple biological processes and disease conditions. Model-based research, especially using gene knockout (KO) or conditional knockout (CKO) mouse models, has revealed its significance in diseases like PH, cancer, and vascular diseases. These findings provide potential therapeutic strategies, such as targeting Smyd2 or its related pathways, for the prevention and treatment of these diseases.