Chronic kidney disease (CKD) is in high prevalence all over the world. Renal fibrosis is the common feature in all kinds of CKD. However, the underlying mechanisms of renal fibrosis are still poorly understood. Fatty acid metabolism is a key pathway to supply energy to tubular cells. However, the regulatory machinery has not been fully investigated. In this study, we found the inhibition of fatty acid metabolism in renal tubular epithelial cells, which positively correlated with renal fibrosis. LKB1-AMPK signaling pathway was also inhibited. Interestingly, we found β-catenin blocked LKB1-AMPK signaling pathway through inhibition of Sumoylation of LKB1. Notably, we also found Sumo3 plays a decisive role in the Sumoylation modification of LKB1. Gene ablation of β-catenin in tubular cells (Ksp-β-catenin−/−) greatly upregulated LKB1-AMPK signaling, restored fatty acid metabolism, and ameliorated renal fibrosis. Overexpression of Sumo3 could resist Wnt1-induced mitochondrial dysfunction and renal fibrosis. These results suggest that Sumoylation modification of LKB1 plays a key role in protecting against renal fibrosis, and β-catenin modulates LKB1 signaling through regulating Sumo3. Our study provides new mechanisms to energy metabolism in renal tubular cells and provides a new therapeutic target for treating renal fibrosis.