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

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.