Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression PMID: 39511379

ADC Targets in Oncology

2026-04-10

Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression

Nat Cell Biol. 2024 Dec;26(12):2099-2114. doi: 10.1038/s41556-024-01540-6.

Tian Zhang ¹ ² , Weixin Fu ¹ ³ , Haosong Zhang ¹ ² , Jianlong Li ¹ ² , Beizi Xing ¹ ² , Yuping Cai ¹ , Mengmeng Zhang ¹ , Xuheng Liu ¹ ² , Chunting Qi ¹ , Lihui Qian ¹ , Xinbo Hu ¹ , Hua Zhu ¹ , Shuailong Yang ¹ ² , Min Zhang ¹ ² , Jianping Liu ¹ , Ganquan Li ¹ ² , Yang Li ¹ ² , Rong Xiang ¹ , Zhengqiang Qi ¹ , Junhao Hu ¹ , Ying Li ¹ , Chengyu Zou ¹ ⁴ , Qin Wang ⁵ , Xia Jin ⁶ , Rui Pang ⁶ ⁷ , Peiying Li ⁶ ⁷ , Junli Liu ⁸ , Yaoyang Zhang ¹ ⁴ , Zhaoyin Wang ¹ , Zheng-Jiang Zhu ⁹ ¹⁰ , Bing Shan ¹¹ , Junying Yuan ¹² ¹³

Affiliations

1. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
2. University of Chinese Academy of Sciences, Beijing, China.
3. Nankai University, Tianjin, China.
4. Shanghai Key Laboratory of Aging Studies, Shanghai, China.
5. Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
6. Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
7. Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
8. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
9. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
10. Shanghai Key Laboratory of Aging Studies, Shanghai, China. [email protected].
11. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
12. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
13. Shanghai Key Laboratory of Aging Studies, Shanghai, China. [email protected].

Abstract

It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates Insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine-a natural polyamine exhibiting health-protective and anti-ageing effects-but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, Insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.