Metabolic homeostasis regulated by blood flow is a crucial evolutionary switch determining the outcome of tissue repair (regeneration vs. fibrosis) and cancer risk

This hypothesis proposes that the core driving force behind the evolutionary loss of limb regeneration ability in animals lies in the dramatic increase in local blood flow resulting from the upgrading of the circulatory system. Strong blood flow rapidly eliminates the inherent hypoxic microenvironment after injury, disrupting the "hypoxia-glycolysis metabolic program" necessary to initiate complete regeneration. This program, by producing lactic acid and reactive oxygen species (ROS), coordinates macrophage M2 polarization to inhibit fibrosis on the one hand, and promotes retinoic acid (RA) synthesis to drive cell dedifferentiation and proliferation on the other. However, in the absence of precise exogenous immune surveillance, this highly plastic and proliferative program carries a high carcinogenic risk. Therefore, higher mammals have evolved a strategy of rapid fibrotic scar repair as an alternative to perfect regeneration, representing a key trade-off between "regenerative potential" and "cancer risk" in evolution.