The Emergency Regenerative Defense Program (ERDP): A Two-Step Non-Genetic Mechanism Driving Immediate Human Regeneration

This is a preprint version of the manuscript. In regenerative medicine, tissue recovery after injury is generally believed to require several days to weeks. However, in clinical practice, rapid improvements in pain and function are often observed within only a few minutes. Such phenomena suggest the existence of an immediate and systemic physiological response that cannot be explained by current regeneration models. In our previous study, we identified a systemic program termed the Emergency Regenerative Defense Program (ERDP), in which localized mechanical stimulation activates the regenerative, immune, and metabolic systems throughout the body within 10 minutes after stimulation and maintains this activation for at least two hours. To elucidate the underlying molecular mechanism, we reanalyzed the plasma and exosomal proteome datasets obtained in the previous report. The analysis identified 34 plasma proteins that disappeared within 10 minutes after ERDP activation and were not re-detected at two hours. Functional classification of these proteins suggested that ERDP operates through two complementary processes: (1) Limiter Release, which restarts the cell cycle by removing inhibitory molecules such as HINT1 and Nogo; and (2) Pre-stored Activation, in which molecular resources already stocked within the body, including HSPA1A, VDAC2, and Nucleolin, are mobilized to initiate repair and metabolic reconstruction without requiring new gene transcription. Through these two coordinated processes, ERDP functions as an immediate physiological program that, in emergencies, simultaneously reactivates the regenerative, immune, and metabolic systems without involving gene expression. This study proposes the existence of a stock-driven, gene-expression-independent immediate physiological system, providing a new conceptual framework for regenerative medicine, immune regulation, and aging research.