Gut microbiota-derived lysine phenylacetylation impairs mitochondrial function and is alleviated by SIRT3 PMID: 42341761

ADC Targets in Oncology

2026-04-10

Gut microbiota-derived lysine phenylacetylation impairs mitochondrial function and is alleviated by SIRT3

Cell Metab. 2026 Jun 24:S1550-4131(26)00226-3. doi: 10.1016/j.cmet.2026.05.016.

Wei Du ¹ , Jun-Yu Xu ² , Yufeng Li ³ , Mingya Zhang ⁴ , Yidan Huang ⁵ , Shaoqian Zhao ⁶ , Ying Zhou ¹ , Lei Zhao ⁷ , Kexin Xu ³ , Linhui Zhai ⁸ , Wensi Zhao ⁸ , Jia Liu ³ , Jiahui Ni ³ , Junxiao Dai ⁸ , Tianxian Liu ⁸ , Jie Hong ⁶ , Haowen Jiang ⁹ , Shuliang Zhao ¹⁰ , Jian Zhang ¹¹ , Lu Zhou ¹² , Ji-Qiu Wang ⁶ , Bin-Cheng Yin ¹ , Rui-Xin Liu ⁶ , Jingya Li ¹³ , Bang-Ce Ye ¹⁴ , Minjia Tan ¹⁵

Affiliations

1. Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China. Electronic address: [email protected].
3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, Fudan University, Shanghai 201203, China.
5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
6. Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China.
7. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
8. Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
9. Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China.
10. Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
11. Department of Pharmaceutical and Artificial-Intelligence Sciences, Institute of Medical Artificial Intelligence, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
12. School of Pharmacy, Fudan University, Shanghai 201203, China.
13. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
14. Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: [email protected].
15. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].

Abstract

Disturbances in the gut microbiota (GM) contribute to the pathogenesis of various prevalent metabolic disorders. Short-chain fatty acids act as signaling molecules and donors for host post-translational modifications. Here, we report a novel type of lysine modification, phenylacetylation (Kpaa), derived from the phenylalanine-dependent phenylacetic acid (PAA) metabolic pathway of the GM. Hepatic Kpaa levels were significantly elevated in mice with high-fat-diet-induced obesity and were reduced by the deacetylase Sirtuin 3 (SIRT3). Proteome-wide substrates were significantly associated with mitochondria. PAA disrupted mitochondrial function and impaired Insulin signaling. Mechanistically, PAA-induced K481paa of HSP60 triggered the mitochondrial unfolded protein response, which could be reversed by SIRT3. Finally, relatively low levels of hepatic SIRT3 in adults with obesity and metabolic dysfunction-associated steatohepatitis (MASH) were negatively correlated with increased Kpaa levels. Together, our study uncovered a microbiota-derived lysine acylation modification underlying its biological relevance in the development of metabolic dysfunction-associated steatotic liver disease (MASLD)/MASH.

Keywords

HSP60; MASLD/MASH; SIRT3; gut microbiota; lysine phenylacetylation; mitochondrial function; phenylacetic acid; phenylalanine; post-translational modification; proteomics.