Oral Nano-Oxygen Modulates the Intestinal HIF-2α/NEU3/Ceramide Axis to Mitigate NAFLD

Abstract The intestinal hypoxia-inducible factor-2α (HIF-2α)/neuraminidase 3 (NEU3)/ceramide axis has emerged as an important regulator of gut–liver communication in nonalcoholic fatty liver disease (NAFLD). However, systemic inhibition of HIF-2α may interfere with hepatic glucose homeostasis, highlighting the need for tissue-restricted modulation through this pathway. Here, we developed an orally administered perfluorohexane-albumin nano-oxygen formulation (PNP(O)) designed to retain oxygen within the intestinal compartment and provide sustained local oxygen release. PNP(O) exhibited favorable gastrointestinal stability, prolonged oxygen-release capacity, and predominant intestinal retention following oral administration. Treatment with PNP(O) was associated with reduced intestinal HIF-2α and NEU3 expression and decreased intestinal and hepatic ceramide levels, accompanied by alleviation of hepatic steatosis and fibrosis in high-fat diet-fed mice. Importantly, PNP(O) improved glucose tolerance without inducing the metabolic disturbances associated with systemic HIF-2α inhibition. These findings support a potential link between local intestinal oxygen availability, suppression of the HIF-2α/NEU3 axis, and attenuation of enterohepatic ceramide signaling, while the causal contribution of intestinal reoxygenation requires further direct validation. Overall, this study provides a concept for spatially restricted modulation of the gut–liver axis through oral oxygen delivery and highlights the potential of local microenvironmental regulation as an alternative to systemic target inhibition for metabolic diseases.