Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice

ABSTRACT: Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4) is an enzyme that removes sialic acids from glycoconjugates, while the function of NEU4 in chronic progressive fibrosis has not been clearly explored. Here, we find that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation was observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial-to-mesenchymal transition and the production of pro-fibrotic cytokines in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4254-388aa interacts with Yes-associated protein YAP at WW2 domain (231-263aa), promotes its translocation to the nucleus, activates its target genes, and consequently contributes to renal fibrosis. 3,5,6,7,8,3ʹ,4ʹ-Heptamethoxyflavone, a natural compound, is identified as a novel inhibitor of NEU4 and effectively protects mice from renal fibrosis in a NEU4-dependent manner. Collectively, our findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Renal Fibrosis

SUBMITTER: Ping-Ting Xiao  

LAB HEAD: Ping-Ting Xiao

PROVIDER: PXD051726 | Pride | 2025-05-06

REPOSITORIES: Pride