The major findings of this work include: i) NEU4 was significantly elevated in TECs of fibrotic kidneys from human and mice; ii) NEU4 was identified as a promotor of renal fibrosis using adeno‐associated virus; iii) mechanistically, The 254–388 amino acid of NEU4 was found to interact with Yap within the amino acid region 231–263, resulting in the translocation of Yap into the nucleus and subsequent upregulation of yap‐targeted genes (CTGF); and iv) HMF was screened as a novel inhibitor of NEU4 and effectively alleviated renal fibrosis. Here, CCN2 is linked to renal fibrosis.