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Zanthoxylum bungeanum essential oil (ZBO) is a natural plant volatile oil with diverse bioactivities, but its anti-obesity effects and potential associations remain unclear. Methods: HFD-induced obese (DIO) mice were evaluated to determine the effects of ZBO. Physiological parameters, glucose tolerance, and serum biochemical markers were assessed. Potential correlates were explored using a multi-omics approach, including integrated serum untargeted metabolomics, 16S rRNA gene sequencing, and RT-qPCR analysis of key genes involved in lipid metabolism in the liver and white adipose tissue. Results: ZBO significantly mitigated HFD-induced body weight gain, visceral adiposity, hepatic steatosis, dyslipidemia, and glucose intolerance. Metabolomics indicated that ZBO administration was associated with alterations in the serum metabolic landscape, particularly in pathways related to fatty acid metabolism and AMPK\/PPAR-\u03b1 signaling. Consistently, ZBO treatment was associated with upregulated mRNA expression of lipid-oxidizing genes (AMPK, PPAR-\u03b1, CPT1) and downregulated lipogenic genes (SREBP-1c, ACC, FAS, SCD1, LPL). 16S rRNA sequencing suggested that ZBO was associated with increased gut microbial diversity, decreased the Firmicutes\/Bacteroidota ratio, and enriched beneficial taxa (e.g., Ligilactobacillus, Alistipes) while suppressing pro-inflammatory genera. Correlation analysis established robust associations between ZBO-modulated microbes and key fatty acid metabolites, particularly acylcarnitines and AMPK\/PPAR-\u03b1-related intermediates. Conclusions: Collectively, these multi-omics data suggest that ZBO administration is associated with remodeling of the gut microbiota and correlated changes in fatty acid metabolic pathways. These findings provide preliminary preclinical evidence supporting further investigation of ZBO in the context of dietary strategies for alleviating HFD-induced obesity.<\/jats:p>","DOI":"10.3390\/nu18182950","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:05:43Z","timestamp":1788941143000},"page":"2950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zanthoxylum bungeanum Essential Oil Alleviates Obesity and Dysregulated Lipid Metabolism in Diet-Induced Obese Mice: A Multi-Omics Study Linking Gut Microbiota to Fatty Acid Metabolism"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9636-0964","authenticated-orcid":false,"given":"Luchuanyang","family":"Sun","sequence":"first","affiliation":[{"name":"School of Food and Bio-Engineering, Xihua University, Chengdu 610039, 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