Although fibrotic kidney displays severer Klotho loss due to aberrant DNMT1/3a induction and Klotho promoter hypermethylation, Rhein effectively corrects these epigenetic alterations, leading to the reversal of Klotho loss, interruption of profibrotic signaling and protein expressions, and the alleviation of renal fibrosis (Fig. 7). The gene discussed is DNMT1; the disease is renal fibrosis.