Current therapies targeting either inflammation or fibrosis alone are ineffective in preventing chronic inflammation progressing towards fibrosis and kidney failure; anti-inflammatory therapies are profibrotic while anti-fibrosis treatment hampers resolution of the inflammation. We have identified a transcription factor complex, the β-catenin/TCF/Foxo1 axis, at the centre of crosstalk among multiple signal pathways including TGF-β crosstalking with Wnt. Targeting the β-catenin/TCF/Foxo1 axis effectively switches off profibrotic genes while switches on anti-inflammatory signals at the same time in fibro-inflammatory disease of kidney and other organs. These findings provide a novel solution in overcoming the current hurdle in treatment of chronic kidney disease.