Open Access

REVIEW

Targeting the cytokine-epigenetic axis: a new paradigm and prospects for disease treatment

Yuyue Luo^1,#, Yikan Zheng^2,#, Jie Qin^1,#, Jinwei Liu², Yuhan Ma², Jingda Li³, Jun Li⁴, Wenlong Sun^1,*, Qian Zhang^2,*, Mengyao Li^5,6,*

1 School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
2 First Clinical Medical College, Inner Mongolia Medical University, Hohhot, China
3 College of Life Science, Yangtze University, Jingzhou, China
4 College of Pharmacy, Inner Mongolia Medical University, Hohhot, China
5 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
6 Shanghai Key Laboratory for Cancer Systems Regulation and Clinical Translation, Shanghai Jiading District Central Hospital, Shanghai, China

* Corresponding Authors: Wenlong Sun. Email: ; Qian Zhang. Email: ; Mengyao Li. Email:
# These authors contributed equally to this work as the first author

European Cytokine Network 2026, 37(2), 97-119. https://doi.org/10.32604/ecn.2026.082885

Received 24 March 2026; Accepted 29 May 2026; Issue published 30 June 2026

Abstract

Cytokines, as key signaling molecules, are involved in the regulation of physiological and pathological processes such as inflammation, immunity, and cell growth. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, enable precise control of gene expression without changing the DNA sequence. Recent studies have revealed that cytokines interact with epigenetic regulation to form a dynamic and complex “cytokine-epigenetic axis”. Through metabolic reprogramming and regulation of epigenetic enzyme activity, this axis affects gene expression patterns at both transcriptional and post-transcriptional levels, thereby contributing to the initiation and progression of various diseases, including autoimmune diseases, neurodegenerative diseases, neuropsychiatric disorders, metabolic diseases, and cancer. Targeting this regulatory axis by combining interventions on upstream cytokine signaling and downstream epigenetic enzymes represents a new precision therapeutic strategy for overcoming resistance to monotherapy and achieving disease-modifying treatment. This review describes how cytokines regulate epigenetic modification substrates through metabolic reprogramming and directly regulate epigenetic enzyme activity via JAK-STAT, NF-κB, and TGF-β/Smad pathways; how this axis drives disease chronicity and therapy resistance across autoimmune, neurodegenerative, metabolic, and neoplastic diseases by establishing long-lasting functional reprogramming; and emerging strategies targeting this axis through combined interventions, precision medicine, and disease memory reprogramming.

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Keywords

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