Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation

Yibo Zuo; Qin Wang; Wanying Tian; Xinhe Wang; Zhijin Zheng; Wei He; Renxia Zhang; Qian Zhao; Ying Miao; Yukang Yuan; Tingting Zhang; Qun Cui; Yuerong Zhang; Chunyan Liu; Haiyan Zhou; Hui Zheng

doi:10.1016/j.cell.2026.01.023

Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation

Cell. 2026 Feb 27:S0092-8674(26)00110-8. doi: 10.1016/j.cell.2026.01.023. Online ahead of print.

Authors

Yibo Zuo¹, Qin Wang², Wanying Tian³, Xinhe Wang², Zhijin Zheng³, Wei He¹, Renxia Zhang³, Qian Zhao³, Ying Miao², Yukang Yuan¹, Tingting Zhang¹, Qun Cui³, Yuerong Zhang², Chunyan Liu², Haiyan Zhou², Hui Zheng⁴

Affiliations

¹ Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan-Chongqing Joint Key Laboratory for Pathology and Laboratory Medicine and Jinfeng Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China; The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
² Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan-Chongqing Joint Key Laboratory for Pathology and Laboratory Medicine and Jinfeng Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China.
³ The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
⁴ Department of Laboratory Medicine, Institute of Laboratory Medicine, Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan-Chongqing Joint Key Laboratory for Pathology and Laboratory Medicine and Jinfeng Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China; The First Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China; Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China; Collaborative Innovation Center of Hematology, Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: huizheng@uestc.edu.cn.

PMID: 41763198
DOI: 10.1016/j.cell.2026.01.023

Abstract

Glycolysis is a central metabolic pathway that converts glucose into pyruvate. Although pyruvate has been well documented to be a key and terminal metabolite of glycolysis with both energetic and biosynthetic roles, its non-metabolic functions remain unexplored. Here, we report a pyruvate-mediated protein post-translational modification (PTM), protein pyruvylation. We reveal that high glucose-upregulated glycolysis promotes signal transducer and activator of transcription 1 (STAT1) pyruvylation at Lys201 (K201), which blocks STAT1 and signal transducer and activator of transcription 2 (STAT2) interaction, thus suppressing type I interferon (IFN-I) signaling and antiviral immune activity. Consequently, STAT1-K201R knockin mice exhibit enhanced IFN-I antiviral immunity. Importantly, high glucose promotes STAT1 pyruvylation and attenuates immune response to either virus infection or IFN-I treatment in humans. This study identifies the protein pyruvylation modification, reveals a non-metabolic function of the metabolite pyruvate, and provides insights into how high glucose impairs IFN-I antiviral immunity through pyruvate, offering strategies to improve IFN-I immune activity for both preventing and treating viral infections.

Keywords: STAT1; antiviral immunity; innate immunity; interferon; pyruvate; pyruvylation.