Modeling reveals temperature compensation and entrainment in the peroxiredoxin-based redox oscillator as an ancient circadian timekeeper.

Peroxiredoxins (PRXs) are antioxidant enzymes that exhibit ∼24 h redox-state oscillations across diverse life forms. These non-transcriptional rhythms operate independently of the canonical transcription-translation feedback loops, suggesting an ancient, conserved timekeeping mechanism. However, whether this redox oscillator meets the core circadian criteria-entrainment and temperature compensation-remains a key question. To address this, we developed and calibrated a mathematical model of the mitochondrial PRX/ sulfiredoxin/thioredoxin redox cycle using physiologically meaningful parameters. The model quantitatively reproduced experimental redox oscillations inA. thaliana, D. melanogaster, andM. musculus. Simulations revealed that the PRX redox oscillator possesses both temperature-compensated periodicity and the capacity for entrainment by periodic thermal and oxidative signals, thereby fulfilling the core criteria of a circadian clock. The inverse angular speed, when integrated over the closed orbit, is largely temperature-invariant, thus providing a mathematical basis for the observed period stability. The calculated phase response curves, which show phase-dependent shifts, together with the broad Arnold tongue for 1:1 resonance, demonstrate a substantial entrainment range that enables the internal rhythm to robustly lock onto periodic environmental Zeitgebers.