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.