The ROS Gatekeeper Hypothesis: A Conceptual Framework for Gasotransmitter Signaling in Pressure Ulcers

Pressure ulcers are a major clinical problem in patients with severe immobility; however, their pathophysiology extends beyond mechanical pressure and localized ischemia. Repetitive ischemia–reperfusion promotes sustained reactive oxygen species (ROS) production, leading to persistent inflammation, mitochondrial dysfunction, metabolic stress, and chronic wound refractoriness. In this review, we propose the ROS Gatekeeper Hypothesis, in which a ROS-dominant redox microenvironment functions as the central determinant of signaling permissiveness for gaseous signaling molecules. Within this framework, nitric oxide (NO) serves as the principal redox-responsive signaling axis, whereas hydrogen sulfide (H2S) and carbon monoxide (CO) function as complementary redox-responsive modulators whose biological effects depend on the surrounding redox environment. Under ROS-dominant conditions, NO bioavailability is reduced through superoxide scavenging and endothelial nitric oxide synthase (eNOS) uncoupling, while progressive oxidative stress is proposed to drive a transition toward a redox-constrained state in which responsiveness to all three gasotransmitters becomes increasingly limited. Accordingly, therapeutic efficacy is proposed to depend on preservation or restoration of signaling permissiveness rather than gasotransmitter abundance alone. The ROS Gatekeeper Hypothesis provides a unified conceptual framework for interpreting heterogeneous therapeutic responses and guiding future stage-specific, redox-oriented therapeutic strategies for chronic wounds.