Unconventional Reactive Oxygen Generation and Biological Outcomes

Abstract

Reactive oxygen species (ROS, 1O2, O2·, OH·, and H2O2) are widely recognized for their dual roles in biological systems, contributing to both cellular signaling and oxidative stress-induced damage. While conventional ROS generation pathways have been extensively explored, emerging evidence highlights unconventional mechanism of ROS generation and their non-canonical biological consequences. In this presentation, I will deliver three recent studies that unveil novel aspects of photoinduced ROS generation and their biological outcomes. First, rational design strategy for ROS generation under hypoxic condition will be discussed, achieved via water photooxidation.1 This oxidative photocatalysis at cellular membranes can initiate non-canonical pyroptosis, a unique form of inflammatory cell death distinct from classical pathway. Notably, in-vivo mouse models confirmed the introduction of immunogenic cell death. In the next study, a spin-flip based electron transfer mechanism is uncovered, enabling efficient singlet oxygen generation from polyaminoglycerol, bypassing the traditional Type II energy transfer mechanism, and leading to potent antibacterial effect.2 This finding paves the way for the design of biocompatible aliphatic organic photosensitizers. Finally, this unconventional singlet oxygen generation also contributes to revealing a hidden route of protein damage through oxygen-confined photooxidation within microenvironment, emphasizing how spatially restrict ROS can induce site-selective biomolecular damage.3 Such photooxidative mechanism may represent a latent oxidation pathway in human tissues directly exposed to visible light, such as skin and eyes. Together, these works highlight the importance of revisiting ROS generation beyond classical paradigms and understanding their spatial, mechanistic, and biological specificity. This presentation will provide an integrative view of these unconventional ROS pathways and discuss their implications in cell death, immunogenicity, therapeutic applications, and protein damages under visible light.