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Nevertheless, the intricate interplay between lipid droplet autophagy and mitochondrial function under hypoxic conditions remains largely uncharted territory. Constructing NAFLD mouse models at altitudes of 2200 meters and 4500 meters and simultaneously culturing hepatocytes under oxygen concentrations of 21% and 1%, with the addition of oleic acid to induce lipid accumulation. A comprehensive evaluation of the NAFLD mice at different altitudes was conducted, including a combination of NMR, PAS, and Oil Red O staining, immunofluorescence, qPCR, flow cytometry, ELISA, electron microscopy, and cellular energy metabolism experiments. The high-altitude, high-fat diet group exhibited a reduction in lipid deposition and glycogen content, an increase in lipid droplet autophagy, and a decrease in mitochondrial damage and inflammatory injury when compared to the moderate-altitude, high-fat diet group. The 1% O<jats:sub>2<\/jats:sub>\u2009+\u2009oleic acid group exhibited enhanced lipid droplet autophagy and increased cellular adaptation in comparison to the 21% O<jats:sub>2<\/jats:sub>\u2009+\u2009oleic acid group. This study revealed that hypoxic conditions enhanced lipid droplet autophagy, reduced glycolipid accumulation, and alleviated mitochondrial damage in NAFLD mice.<\/jats:p>","DOI":"10.1371\/journal.pone.0331305","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T17:38:02Z","timestamp":1758821882000},"page":"e0331305","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A new investigation of nonalcoholic fatty liver disease: Effects of hypoxia on mitochondrial function and lipid droplet 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