Our results indicate that HA (1) promoted renal fibrosis progression; (2) activated ROS-mediated TGFβ/SMAD signaling; (3) caused a redox imbalance by impairing the antioxidant system; and (4) increased the degradation of ubiquitinated NRF2 by facilitating NRF2–KEAP1–CUL3 interactions, in HK-2 cells and 5/6NX rats. This evidence concerns the gene CUL3 and renal fibrosis.