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Background: To explore the biological effects of CASC11 on aggravating diabetic nephropathy (DN) by regulating FoxO1 (forkhead transcription factor O1). Methods: Serum levels of CASC11 and FoxO1 in DN patients were detected. The possibility of CASC11 in predicting the onset of DN was analyzed by depicting ROC curves. Correlation between CASC11 and FoxO1 was evaluated by Pearson correlation test. After intervening CASC11 and FoxO1 levels, we found that changes in proliferative and migratory abilities in high glucose (HG)induced kidney mesangial cells were determined respectively. Protein levels of TGF-b1 and Smads regulated by both CASC11 and FoxO1 were examined by Western blot. Results: A high expression CASC11 but a low expression of FoxO1were in serum of DN patients, showing they were a negative correlation. Hence, CASC11 may be a diagnostic marker for DN. It attenuated proliferative and migratory abilities of HG-induced kidney mesangial cells, but the above inhibitory effects of CASC11 could be abolished by overexpression of FoxO1. Besides, protein levels of TGF-b1 and Smads were positively regulated by CASC11, but Smads regulation were reversed such changes. Conclusion: Through activating the TGF-b1/Smads signaling, CASC11 inhibits FoxO1 expression and thus induces the aggravation of DN.