Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology

Qiaoyan Wu; Na Cui; Li Gao; Zhihui Lu; Xiang Ao; Rui Pang; Xingyan Li; Heling Pan; Daichao Xu; Peiying Li; Junying Yuan; Chengyu Zou

doi:10.1172/JCI207077

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Wu, Q. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Cui, N. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Gao, L. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Lu, Z. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Ao, X. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Pang, R. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Li, X. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Pan, H. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Xu, D. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Li, P. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Yuan, J. in: PubMed | Google Scholar

¹Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

²Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

³Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Find articles by Zou, C. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI207077.
Copyright © 2026, Wu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published September 1, 2026 - Version history

Regulatory T (Treg) cells hold great promise as next-generation therapeutics for autoimmune diseases. However, maintaining their functional persistence within inflamed tissues remains a major translational challenge. Using an in vitro system that recapitulates the inflammatory CNS milieu of multiple sclerosis (MS), together with a pooled shRNA screen, we identify necroptotic signaling as a key driver of Treg cell death, thereby compromising Treg functional persistence under inflammatory conditions. We further demonstrate that Treg cells in both a mouse model of MS and patients with MS exhibit a preferential susceptibility to RIPK1 kinase-dependent necroptosis. Mechanistically, a FOXP3-driven low-glucose metabolic program renders Treg cells intrinsically susceptible to necroptosis by limiting O-GlcNAc modification on RIPK1. This vulnerability is not shared by conventional T cells under comparable inflammatory conditions. Finally, in combined with adoptive Treg cell transfer, we show that selective inhibition of necroptosis in Treg cells enhances their survival and suppressive function at sites of active inflammation, thereby reducing autoimmune pathology in mouse models of MS and systemic lupus erythematosus. Together, these findings identify necroptotic cell death as a barrier to Treg persistence within inflamed tissues and highlight the therapeutic potential of necroptosis-resistant Treg cells for the treatment of autoimmune diseases.

Version 1 (September 1, 2026): In-Press Preview

Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology

Qiaoyan Wu,¹ Na Cui,¹ Li Gao,² Zhihui Lu,¹ Xiang Ao,¹ Rui Pang,³ Xingyan Li,¹ Heling Pan,¹ Daichao Xu,¹ Peiying Li,³ Junying Yuan,¹ and Chengyu Zou¹

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Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology

Qiaoyan Wu,1 Na Cui,1 Li Gao,2 Zhihui Lu,1 Xiang Ao,1 Rui Pang,3 Xingyan Li,1 Heling Pan,1 Daichao Xu,1 Peiying Li,3 Junying Yuan,1 and Chengyu Zou1

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Qiaoyan Wu,¹ Na Cui,¹ Li Gao,² Zhihui Lu,¹ Xiang Ao,¹ Rui Pang,³ Xingyan Li,¹ Heling Pan,¹ Daichao Xu,¹ Peiying Li,³ Junying Yuan,¹ and Chengyu Zou¹