Tfpi2, or Tissue Factor Pathway Inhibitor 2, is a Kunitz-type protease inhibitor. It is involved in multiple biological processes, such as regulating cell self-renewal, immune cell polarization, and cell-cell interactions. It activates signaling pathways like c-Jun N-terminal kinase-STAT3, STAT6, and is associated with the AP-2α/PPARγ axis, TGF-β2/Smad signaling, and TWIST-integrin α5 pathway, playing a significant role in tumorigenesis, diabetes-related cardiovascular and renal diseases [1-5].

In glioblastoma, TFPI2 promotes GSC self-renewal and tumor growth via the c-Jun N-terminal kinase-STAT3 pathway and triggers microglia infiltration and immunosuppressive polarization through the TFPI2-CD51-STAT6 axis [1]. In diabetic atherosclerosis, TFPI2 hypermethylation promotes disease progression through the Ap2α/PPARγ axis [2]. In breast cancer, TFPI2 suppresses tumor progression by inhibiting the TWIST-integrin α5 pathway [3]. In diabetic nephropathy, TFPI2 promotes endothelial-mesenchymal transition by interfering with the interaction of TGF-β2 pathway regulators [4]. In melanoma, TFPI2 downregulation weakens perivascular migration [5]. In post-myocardial infarction in diabetic mice, TFPI2 overexpression promotes recovery by inducing M2 polarization and inhibiting fibroblast activation through the TFPI2-PPARγ axis [6]. In clear cell renal carcinoma, serum TFPI2 is elevated and may serve as a biomarker [7]. In diabetic neointimal hyperplasia, PARP1 accelerates the process by downregulating TFPI2 [8].

In conclusion, Tfpi2 is a key regulator in various biological processes and diseases. Gene knockout and other loss-of-function models in mice have been crucial in revealing its role in glioblastoma, diabetes-related cardiovascular and renal diseases, breast cancer, melanoma, and post-myocardial infarction recovery. These studies provide insights into its potential as a therapeutic target and biomarker in these disease areas.