Fgf12, a member of the fibroblast growth factor homologous factors (FHF) subfamily also known as the FGF11 subfamily, is an intracrine factor. Structurally, its core domain has a classical β-trefoil structure similar to other FGF proteins. It is expressed in various tissues, especially in excitable cells. Fgf12 is involved in multiple functions such as interacting with sodium channels, signaling proteins, regulating the cytoskeletal system, and ribosome biogenesis. It also activates signaling cascades to prevent apoptosis [2].

In liver fibrosis mouse models, Fgf12 was up-regulated in nonparenchymal liver cells, especially hepatic macrophages. Myeloid-specific Fgf12 knockout mice showed protection against BDL-induced and CCL4-induced liver fibrosis. Fgf12 deletion decreased the population of certain macrophages and reduced proinflammatory cytokines and chemokines. It promoted proinflammatory activation of macrophages and HSC activation mainly through the monocyte chemoattractant protein-1/chemokine (C-C motif) receptor 2 axis, and its regulation of macrophage activation was mainly mediated through the Janus kinase-signal transducer of activators of transcription pathway [1].

In psoriasis, specific loss of Fgf12 in keratinocytes in an IMQ-induced psoriasis model alleviated psoriasis-like symptoms and reduced proliferation. In vitro, knockdown of Fgf12 arrested the cell cycle and inhibited cell proliferation, predominantly regulating the p53 signaling pathway [3].

In doxorubicin-induced cardiomyocytes, Fgf12 overexpression alleviated myocardial injury by inhibiting mitochondria-dependent ferroptosis through activation of the FGFR1/AMPK/NRF2 signaling [4].

In pulmonary arterial hypertension murine models, FGF12 expression was reduced in pulmonary arterial smooth muscle cells (PASMCs). FGF12 knockdown blocked the antiproliferative and prodifferentiation effect of BMP on human PASMCs. Smooth muscle cell-specific FGF12 overexpression protected from chronic hypoxia-induced PAH development, pulmonary vascular remodeling, and right ventricular hypertrophy [5].

In conclusion, Fgf12 plays crucial roles in multiple biological processes and disease conditions. Studies using gene knockout mouse models have revealed its functions in liver fibrosis, psoriasis, cardiomyocyte injury, and pulmonary arterial hypertension. These findings highlight Fgf12 as a potential therapeutic target in these disease areas.