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Here, we aimed to investigate whether 18\u03b2-GA attenuates obesity-associated white adipose tissue (WAT) inflammaging and to clarify the molecular events responsible for its protective effects. Using a high-fat diet mouse model together with cultured adipose progenitor cells (APCs), we found that 18\u03b2-GA significantly mitigated inflammation and cellular senescence in WAT, diminished the expression of senescence-associated secretory phenotype (SASP), and restored APC adipogenic differentiation potential. Network pharmacology analysis pinpointed HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) as a key candidate target, with subsequent experiments confirming that the anti-inflammaging effect of 18\u03b2-GA was comparable to established HMGCR inhibitors. Furthermore, 18\u03b2-GA markedly reduced cholesterol accumulation in WAT, which directly induces APC senescence, suggesting that cholesterol homeostasis regulation represents a key mechanism responsible for its protective activity. Thus, 18\u03b2-GA emerges as a promising nutraceutical agent for combating obesity-driven metabolic disorders and chronic inflammation in WAT.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c02121","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T15:00:02Z","timestamp":1784646002000},"page":"23481-23494","source":"Crossref","is-referenced-by-count":0,"title":["Protective Effects of 18\u03b2-Glycyrrhetinic Acid\nagainst Inflammaging in Adipose Tissue of Diet-Induced Obese Mice"],"prefix":"10.1021","volume":"74","author":[{"given":"Meng","family":"Yang","sequence":"first","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqin","family":"Deng","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzhi","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiheng","family":"Xie","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Lei","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suidong","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonghua","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9033-9099","authenticated-orcid":true,"given":"Xinguang","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Medical University , , ,","place":["Dongguan, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"issue":"11","key":"2026080510101741300_cit1","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1007\/s11892-022-01493-w","article-title":"Cellular\nSenescence in Obesity and Associated Complications:\na New Therapeutic Target","volume":"22","author":"Narasimhan","year":"2022","journal-title":"Curr. Diab. Rep."},{"issue":"3","key":"2026080510101741300_cit2","doi-asserted-by":"publisher","first-page":"C375","DOI":"10.1152\/ajpcell.00379.2020","article-title":"Adipose tissue\ninflammation and metabolic\ndysfunction in obesity","volume":"320","author":"Kawai","year":"2021","journal-title":"Am. J. Physiol. Cell\nPhysiol."},{"issue":"9","key":"2026080510101741300_cit3","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1038\/nm.2014","article-title":"A crucial role for adipose tissue\np53 in the regulation of insulin resistance","volume":"15","author":"Minamino","year":"2009","journal-title":"Nat. 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Food Chem."},{"key":"2026080510101741300_cit12","doi-asserted-by":"publisher","first-page":"156846","DOI":"10.1016\/j.phymed.2025.156846","article-title":"18beta-glycyrrhetinic acid mitigates\nlipotoxicity-induced premature\nsenescence of tubular epithelial cells by activating SIRT1-TFEB signaling","volume":"143","author":"Yang","year":"2025","journal-title":"Phytomedicine"},{"issue":"6257","key":"2026080510101741300_cit13","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/343425a0","article-title":"Regulation of the\nmevalonate pathway","volume":"343","author":"Goldstein","year":"1990","journal-title":"Nature"},{"issue":"1","key":"2026080510101741300_cit14","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1161\/CIRCRESAHA.116.308537","article-title":"Pleiotropic Effects of Statins on\nthe Cardiovascular System","volume":"120","author":"Oesterle","year":"2017","journal-title":"Circ. Res."},{"issue":"1","key":"2026080510101741300_cit15","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41514-023-00128-y","article-title":"Cholesterol biosynthetic pathway\ninduces cellular senescence through ERRalpha","volume":"10","author":"Ziegler","year":"2024","journal-title":"npj Aging"},{"key":"2026080510101741300_cit16","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12997","article-title":"Targeting\nsenescent cells enhances\nadipogenesis and metabolic function in old age","volume":"4","author":"Xu","year":"2015","journal-title":"eLife"},{"issue":"4","key":"2026080510101741300_cit17","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/s41419-022-04752-6","article-title":"Adipose\ntissue aging: mechanisms and therapeutic implications","volume":"13","author":"Ou","year":"2022","journal-title":"Cell Death Dis."},{"issue":"7903","key":"2026080510101741300_cit18","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1038\/s41586-022-04518-2","article-title":"A single-cell\natlas of human and mouse white adipose tissue","volume":"603","author":"Emont","year":"2022","journal-title":"Nature"},{"issue":"1","key":"2026080510101741300_cit19","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/s41419-025-08004-1","article-title":"Adipocyte-specific\nMlkl knockout mitigates obesity-induced\nmetabolic dysfunction by enhancing mitochondrial functions","volume":"16","author":"Tokgozoglu","year":"2025","journal-title":"Cell Death Dis."},{"issue":"19","key":"2026080510101741300_cit20","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202401470R","article-title":"Hypomethylation\nat PANDAR promoter progressively induces senescence in adipocyte precursor\ncells in subjects with obesity and type 2 diabetes","volume":"38","author":"Desiderio","year":"2024","journal-title":"FASEB J."},{"key":"2026080510101741300_cit21","doi-asserted-by":"publisher","first-page":"104840","DOI":"10.1016\/j.phrs.2020.104840","article-title":"18beta-Glycyrrhetinic\nacid acts through hepatocyte nuclear factor 4 alpha to modulate lipid\nand carbohydrate metabolism","volume":"157","author":"Yang","year":"2020","journal-title":"Pharmacol. Res."},{"issue":"7","key":"2026080510101741300_cit22","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1002\/mnfr.201300763","article-title":"18beta-glycyrrhetinic\nacid attenuates anandamide-induced adiposity and high-fat diet induced\nobesity","volume":"58","author":"Park","year":"2014","journal-title":"Mol. Nutr. Food Res."},{"issue":"18","key":"2026080510101741300_cit23","doi-asserted-by":"publisher","first-page":"4854","DOI":"10.1111\/febs.17406","article-title":"Effects of HMG CoA reductase (HMGCR) deficiency on\nskeletal muscle development","volume":"292","author":"Gunasekaran","year":"2025","journal-title":"FEBS J."},{"issue":"2","key":"2026080510101741300_cit24","doi-asserted-by":"publisher","first-page":"158","DOI":"10.2337\/db19-0076","article-title":"Myeloid HMG-CoA\nReductase Determines Adipose Tissue Inflammation, Insulin Resistance,\nand Hepatic Steatosis in Diet-Induced Obese Mice","volume":"69","author":"Takei","year":"2020","journal-title":"Diabetes"},{"issue":"3","key":"2026080510101741300_cit25","doi-asserted-by":"publisher","first-page":"106161","DOI":"10.1016\/j.isci.2023.106161","article-title":"Mevalonate biosynthesis pathway regulates\nthe development and survival of brown adipocytes","volume":"26","author":"Kwon","year":"2023","journal-title":"iScience"},{"issue":"5","key":"2026080510101741300_cit26","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1161\/ATVBAHA.107.160663","article-title":"Effects of\nstatins on adipose tissue inflammation: their inhibitory effect on\nMyD88-independent IRF3\/IFN-beta pathway in macrophages","volume":"28","author":"Abe","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"issue":"5519","key":"2026080510101741300_cit27","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1126\/science.1059344","article-title":"Structural\nmechanism for statin inhibition of HMG-CoA\nreductase","volume":"292","author":"Istvan","year":"2001","journal-title":"Science"},{"issue":"12","key":"2026080510101741300_cit28","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1038\/s42255-020-00320-4","article-title":"Age-associated telomere attrition in adipocyte progenitors\npredisposes to metabolic disease","volume":"2","author":"Gao","year":"2020","journal-title":"Nat. Metab."},{"issue":"3","key":"2026080510101741300_cit29","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s42255-023-00758-2","article-title":"Cholesterol drives\ninflammatory senescence","volume":"5","author":"Kuehnemann","year":"2023","journal-title":"Nat. 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Basic Med. Sci."},{"key":"2026080510101741300_cit33","doi-asserted-by":"publisher","first-page":"101943","DOI":"10.1016\/j.molmet.2024.101943","article-title":"M2 macrophage-derived\nTGF-beta induces\nage-associated loss of adipogenesis through progenitor cell senescence","volume":"84","author":"Zeng","year":"2024","journal-title":"Mol. Metab."},{"issue":"2","key":"2026080510101741300_cit34","doi-asserted-by":"publisher","first-page":"334","DOI":"10.3390\/antiox10020334","article-title":"Signal\nTransducer and Activator of Transcription 3 (STAT3) Suppresses STAT1\/Interferon\nSignaling Pathway and Inflammation in Senescent Preadipocytes","volume":"10","author":"Madani","year":"2021","journal-title":"Antioxidants"},{"issue":"46","key":"2026080510101741300_cit35","doi-asserted-by":"publisher","first-page":"E6301","DOI":"10.1073\/pnas.1515386112","article-title":"JAK inhibition alleviates the cellular senescence-associated\nsecretory phenotype and frailty in old age","volume":"112","author":"Xu","year":"2015","journal-title":"Proc. Natl. Acad. Sci. 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