Targeting NAT10 with Remodelin reshapes the pro-fibrotic microenvironment in renal fibrogenesis via inhibiting exosome oversecretion from tubular cells

Yuqin Tan; Jiaojiao Zheng; Ruojiao Wang; Zhaozhong Zhong; Suxiang Chen; Shuo Lu; Jiayu Zheng; Yongrong Ye; Ning Na; Tong Zheng

doi:10.1016/j.apsb.2026.05.020

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Targeting NAT10 with Remodelin reshapes the pro-fibrotic microenvironment in renal fibrogenesis via inhibiting exosome oversecretion from tubular cells

Journal article

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Targeting NAT10 with Remodelin reshapes the pro-fibrotic microenvironment in renal fibrogenesis via inhibiting exosome oversecretion from tubular cells

Yuqin Tan, Jiaojiao Zheng, Ruojiao Wang, Zhaozhong Zhong, Suxiang Chen, Shuo Lu, Jiayu Zheng, Yongrong Ye, Ning Na and Tong Zheng

Acta pharmaceutica Sinica. B, In Press

2026

DOI: https://doi.org/10.1016/j.apsb.2026.05.020

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Abstract

ac4C

Acetylation

Cell-cell communication

Exosomes

Fibroblast activation

NAT10

Remodelin

Renal fibrosis

Renal fibrosis induces irreversible renal failure and lacks therapies. The tubular epithelial cells (TEC) largely depend on exosomes to create a pro-fibrotic microenvironment, initiating fibroblast activation. However, how exosome secretion of TEC is over-activated during renal fibrogenesis remains unknown. Herein, in vitro high-throughout screen uncovered acetyltransferase NAT10 as promising target to interfere with TEC-fibroblast communication. Further experiments showed that NAT10 was upregulated mainly in the TEC of fibrotic kidneys, and its conditional depletion in TEC alleviated renal fibrosis in vivo. Mechanistically, nuclear NAT10 coordinated with cytoplasmic NAT10 to promote exosome secretion of TEC to induce fibroblast activation via combining mRNA ac4C modification and lysine acetylation (Kac). Moreover, NAT10 upregulated the abundance of exosomal Gli in TEC, which were vital for fibroblast activation. In summary, NAT10-mediated orchestration of ac4C and Kac modifications is the mechanism of over-activated exosome secretion of TEC during renal fibrogenesis. And targeting NAT10 with Remodelin is a promising therapy for renal fibrosis. The nuclear NAT10–ac4C axis cooperates with the cytoplasmic NAT10-Kac to drive TEC-fibroblast communication in kidney. Targeting NAT10 with Remodelin is a promising strategy for renal fibrosis. [Display omitted]

Details

Title: Targeting NAT10 with Remodelin reshapes the pro-fibrotic microenvironment in renal fibrogenesis via inhibiting exosome oversecretion from tubular cells
Authors/Creators: Yuqin Tan - Sun Yat-sen University
Jiaojiao Zheng - Sun Yat-sen University
Ruojiao Wang - Sun Yat-sen University
Zhaozhong Zhong - Sun Yat-sen University
Suxiang Chen - Murdoch University
Shuo Lu - Sun Yat-sen University
Jiayu Zheng - Sun Yat-sen University
Yongrong Ye - Sun Yat-sen University
Ning Na - Sun Yat-sen University
Tong Zheng - Sun Yat-sen University
Publication Details: Acta pharmaceutica Sinica. B, In Press
Publisher: Elsevier B.V.
Identifiers: 991005886394307891
Murdoch Affiliation: Personalised Medicine Centre
Language: English
Resource Type: Journal article

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