AOAH (acyloxyacyl hydrolase) is a lipid-modifying enzyme primarily expressed in phagocytes and epithelial cells that removes secondary fatty acyl chains from bacterial lipopolysaccharide (LPS) lipid A 123. This enzymatic deacylation detoxifies LPS, rendering it less potent at activating macrophages, neutrophils, and endothelial cells 4. AOAH functions as a critical regulator of innate immune responses and the gut microbiota, with roles extending beyond classical LPS metabolism. Disease relevance is substantial across multiple systems. AOAH polymorphisms associate with asthma susceptibility and elevated IgE levels in African ancestry populations 5, with replicated associations in chr7 rhinosinusitis 6. AOAH-deficient mice spontaneously develop pelvic pain, urinary dysfunction, and anxiety-like behaviors via dysbiosis-dependent mechanisms 78. In kidney disease, AOAH protects against fibrosis by inhibiting CD74-macrophage crosstalk in tubular epithelial cells, with expression positively correlating with renal function in CKD patients 9. AOAH also prevents metabolic dysfunction-associated steatotic liver disease by inactivating intestinal LPS 10. Clinically, AOAH represents a novel immunotherapy target; elevated AOAH sensitizes T cell receptors to weak antigens and depletes immunosuppressive lipids, potentiating checkpoint blockade efficacy in multiple tumor models 11.