Circadian rhythms impose temporal organization on immune function, shaping host responses to infection, injury, and chronic disease. While transcriptional control by core clock components such as CLOCK and BMAL1 has been extensively characterized, this paradigm alone cannot explain the rapid and dynamic nature of immune signaling. Emerging evidence identifies post-translational modifications (PTMs)—including phosphorylation, ubiquitination, and acetylation—as critical regulators that confer speed, reversibility, and specificity to inflammatory pathways. Here, we propose the concept of a “Chrono-PTM axis,” in which circadian timing and PTM-dependent signaling are functionally integrated to govern immune activation thresholds. We discuss how PTMs not only regulate core clock machinery but also temporally gate key innate immune pathways, including NF-κB signaling and inflammasome activation, thereby controlling cytokine production at multiple levels. Furthermore, we highlight the role of immunometabolism in supplying essential cofactors that couple cellular energetic states to PTM dynamics, linking metabolic oscillations to inflammatory outputs. Disruption of this axis contributes to the pathogenesis of autoimmune diseases, cancer, and tissue-specific inflammatory disorders. Finally, we outline emerging therapeutic opportunities targeting the Chrono-PTM axis, including chronotherapy and PTM-directed interventions, and identify critical gaps in temporal proteomics and translational studies. Elucidating the integration of circadian and post-translational regulation will provide a unifying framework for understanding immune homeostasis and may enable time-informed precision immunotherapy.
Gu et al. (Wed,) studied this question.