Mbd2, or methyl-CpG-binding domain 2, is a “reader” protein that interprets DNA methylome-encoded information. It is associated with transcriptional regulation, chromatin structure modulation, and is involved in multiple biological processes such as cell differentiation, development, and disease [4]. It can bind to methylated CpG DNA, which is crucial for its functions in various pathways.

In mice, depletion of Mbd2 in macrophages protected against bleomycin-induced pulmonary fibrosis. Mbd2 deficiency attenuated TGF-β1 production and reduced M2 macrophage accumulation in the lung. Mechanistically, Mbd2 bound to the Ship promoter, repressed Ship expression, and enhanced PI3K/Akt signaling to promote the macrophage M2 program [1].

In tumor-related studies, knockdown of MBD2 in LUAD cells (A549 and H1975 cell lines) and B16F10 cells significantly attenuated cell migration, invasion, and epithelial-mesenchymal transition (EMT). MBD2 bound to the methylated CpG DNA within the DDB2 promoter, repressing DDB2 expression to promote tumor metastasis [2].

In cholangiocarcinoma (CCA), MBD2 was upregulated, promoting cell proliferation, migration, and chemoresistance. It interacted with WDR5, bound to the promoter of ABCB1, promoted H3K4 trimethylation through KMT2A, and activated ABCB1 expression [3].

In Th17-dominant asthma, MBD2 expression was increased, and it regulated Th17 cell differentiation by negatively regulating MINK1 [5].

In breast cancer, genetic knockout of Mbd2 in MMTV-PyMT transgenic mice impeded primary tumor growth and lung metastasis, and abrogated the expression of key determinants in epithelial-to-mesenchymal transition and impaired the activation of the PI3K/AKT pathway [6].

In septic acute kidney injury (AKI), inhibition of MBD2 by siRNA or knockout improved the survival rate, attenuated AKI, renal cell apoptosis, and inflammatory factor production. MBD2 directly bound to the promoter region CpG islands of PKCη, and activated PKCη/p38MAPK and the ERK1/2 axis [7].

In conclusion, Mbd2 plays diverse and significant roles in multiple biological processes and disease conditions. Through gene knockout studies in mouse models, its functions in pulmonary fibrosis, tumor metastasis, cholangiocarcinoma progression, Th17-dominant asthma, breast cancer, and septic AKI have been revealed. These findings provide potential therapeutic targets for these diseases by targeting Mbd2 [1,2,3,5,6,7].