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Background: Infantile pneumonia is an acute inflammatory lesion of the lung caused by mycoplasma pneumonia. Indeed, Twist2 signaling pathway controls inflammatory reaction, oxidative stress, and other biological reaction. However, the regulation of Twist2 on the inflammation in infantile pneumonia remains unclear. This study explained that the function and mechanism of Twist2 in infantile pneumonia. Methods: The subjects included the serum samples of 12 patients with infantile pneumonia and normal healthy volunteers from Hunan Children's Hospital. Besides, mice were given with lipopolysaccharide (LPS) into the lung. Moreover, RAW264.7 macrophages were stimulated with LPS for 4 h and added to the culture medium. Results: In present study, in serum of patients with infantile pneumonia or lung tissue of mice model with infantile pneumonia, TWIST2 expression was lessened. Apart from that, TWIST2 protein could reduce the inflammatory reaction in mice model with infantile pneumonia, resulting in an inhibition in lung injury. Conversely, over-expression of TWIST2 also decreased inflammatory reaction in macrophages model via the regulation of FOXO1/NLRP3 pathway. Downregulation of TWIST2 promoted the inflammation in macrophages model by the regulation of FOXO1/NLRP3 pathway. Conclusion: According to the findings, present study have identified that the TWIST2 could reduce the inflammation of infantile pneumonia by NLRP3 inflammasome through the regulation of mitochondrial permeability transition and the induction of FOXO1 expression. [ABSTRACT FROM AUTHOR]