Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence

Lingzhi Li, Ting Xiang, Jingjing Guo, Fan Guo, Yiting Wu, Han Feng, Jing Liu, Sibei Tao, Ping Fu () and Liang Ma ()
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Lingzhi Li: West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases
Ting Xiang: West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases
Jingjing Guo: West China Hospital of Sichuan University
Fan Guo: West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases
Yiting Wu: West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases
Han Feng: Tulane University School of Medicine
Jing Liu: West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases
Sibei Tao: West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases
Ping Fu: West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases
Liang Ma: West China Hospital of Sichuan University, and National Key Laboratory of Kidney Diseases

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1β expression, which thereby alleviate IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.

Date: 2024
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DOI: 10.1038/s41467-024-47315-3

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