Cytokine-epigenetic axis drives disease chronicity and therapy resistance, offering new precision treatment strategies.

Cytokines are crucial signaling molecules governing inflammation, immunity, and cell growth. Epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs precisely control gene expression without altering DNA sequence. Recent insights reveal a complex "cytokine-epigenetic axis" where these two systems interact. This axis contributes to disease initiation and progression by affecting gene expression patterns, driving chronicity and resistance in conditions like autoimmune diseases, neurodegenerative disorders, metabolic diseases, and cancer. Current monotherapies often fall short, necessitating novel, integrated approaches.

This comprehensive review synthesizes recent findings on the "cytokine-epigenetic axis," detailing how cytokines regulate epigenetic modifications through metabolic reprogramming and direct modulation of epigenetic enzyme activity. It describes the molecular events underlying cytokine storm and its evolution into chronic inflammation via immune cell reprogramming. The review delineates how this axis establishes long-lasting functional reprogramming, contributing to disease chronicity and therapy resistance across diverse pathologies. It also explores emerging strategies to target this axis through combined interventions, precision medicine, and disease memory reprogramming.

The review elucidates that cytokines regulate epigenetic modification substrates via metabolic reprogramming and directly influence epigenetic enzyme activity through key signaling pathways, including JAK-STAT, NF-κB, and TGF-β/Smad. This intricate interplay establishes a "cytokine-epigenetic axis" that profoundly affects gene expression at both transcriptional and post-transcriptional levels. This persistent reprogramming contributes to the initiation and progression of various diseases, explaining why monotherapies often fail to achieve lasting remission. The axis's influence on immune cell activation, cytokine network architecture, and intracellular signaling cross-talk is critical in transitioning acute responses to chronic inflammatory states, underscoring its role in trained immunity and disease memory.

This axis drives disease chronicity and therapy resistance across autoimmune diseases, neurodegenerative diseases, neuropsychiatric disorders, metabolic diseases, and cancer by establishing long-lasting functional reprogramming.