Klotho is a membrane-bound protein predominantly expressed in the kidney, where 
it acts as a permissive co-receptor for Fibroblast Growth Factor 23. In its shed 
form, Klotho exerts anti-fibrotic effects in several tissues. Klotho-deficient 
mice spontaneously develop fibrosis and Klotho deficiency exacerbates the 
disease progression in fibrotic animal models. Furthermore, Klotho 
overexpression or supplementation protects against fibrosis in various models of 
renal and cardiac fibrotic disease. These effects are mediated at least 
partially by the direct inhibitory effects of soluble Klotho on TGFβ1 signaling, 
Wnt signaling, and FGF2 signaling. Soluble Klotho, as present in the 
circulation, appears to be the primary mediator of anti-fibrotic effects. 
Similarly, through inhibition of the TGFβ1, Wnt, FGF2, and IGF1 signaling 
pathways, Klotho also inhibits tumorigenesis. The Klotho promoter gene is 
generally hypermethylated in cancer, and overexpression or supplementation of 
Klotho has been found to inhibit tumor growth in various animal models. This 
review focuses on the protective effects of soluble Klotho in inhibiting renal 
fibrosis and fibrosis in distant organs secondary to renal Klotho deficiency. We 
also discuss the structure-function relationships of Klotho domains and 
biological effects in the context of potential targeted treatment strategies.