Urolithin A Attenuates Sleep Deprivation-Induced Neutrophilic Inflammation by Suppression of the ROS-H3K18la Feedback Loop.

Sleep loss drives metabolic and immune dysfunction, yet the epigenetic links to inflammation remain poorly defined. Using larval zebrafish with a continuous-swim paradigm, we demonstrate that acute sleep deprivation (SD) induces sleep fragmentation, systemic oxidative stress, and sustained neutrophilic inflammation─phenotypes associated with elevated histone H3K18 lactylation (H3K18la), an epigenetic modification from glycolytic lactate. Critically, gut microbiota metabolite Urolithin A (UA) exerts potent protection: it downregulates ROS-generating and glycolysis-related genes and reduces intracellular lactate and histone lactylation, collectively disrupting the pathogenic ROS-H3K18la feedback loop. Mechanistically, UA reduces aberrant H3K18la deposition at the il6 and cybb promoters to suppress transcription. Functional assays confirm that UA rescues SD-impaired inflammation resolution, reduces excessive neutrophil recruitment/retention at injury sites, and restores antioxidant homeostasis. These findings identify UA as a multitarget modulator that mitigates SD-associated inflammation via the ROS-H3K18la-inflammation axis, highlighting its translational potential for sleep loss-related immune/metabolic disorders.