P22 A role for polyamine catabolism in epidermal wound healing

Introduction and aims Cutaneous wound healing is a dynamic process requiring tightly regulated, self-limiting mechanisms to achieve precise tissue regeneration and prevent pathology. The coordination of repair – specifically, its precise initiation and termination – is driven by metabolic cues. Polyamines (putrescine, spermidine and spermine) are essential, ubiquitously expressed cations required for normal cellular function and are highly relevant to cellular proliferation and differentiation. This study aimed to identify and characterize the metabolic signalling circuit that controls the initiation and termination of epithelial regeneration during wound healing. Methods We investigated the involvement of polyamine catabolism and its product, acrolein, in wound healing. We used molecular, biochemical and animal model techniques, alongside analysis of human chronic wound samples, to assess the effect of acrolein on key regulatory enzymes and the RNA-binding protein human antigen R (HuR). Results Our data show that following injury, polyamine catabolism is increased and generates acrolein, which acts as a controlled signalling molecule. Acrolein transiently suppresses specific cellular enzymes responsible for protein degradation, thereby preventing the premature breakdown of a key RNA-binding protein, HuR, that post-transcriptionally drives re-epithelialization. As healing progresses, accumulated acrolein subsequently activates a major detoxification pathway (KEAP1–NRF2), which restores acrolein homeostasis and relieves the enzyme inhibition, thereby terminating the repair phase. Disruption of this axis in the rat wound model severely impaired re-epithelialization and tissue regeneration; these defects were rescued by targeted enzyme inhibition. Notably, human chronic wounds exhibited profound dysfunction of this pathway. Conclusions We have identified a novel metabolic circuit in which acrolein, generated by polyamine catabolism, functions as a stage-specific signal. This signal integrates metabolic flux with post-transcriptional regulation (via HuR) to precisely initiate and terminate epithelial regeneration. Our findings redefine acrolein’s role from purely cytotoxic to a critical signalling molecule, providing a mechanistic framework and revealing actionable therapeutic targets for treating human chronic wounds.