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Licorice (Glycyrrhiza uralensis Fisch.) and its bioactive constituents have been reported to protect against nephrotoxicity induced by various nephrotoxic agents. This study aimed to evaluate the protective effects of licorice against VAN-induced nephrotoxicity and to explore the underlying mechanisms both in vivo and in vitro. Methods: Seven groups of male C57BL\/6 mice received different treatments for 7 consecutive days. Blood, fecal and renal tissue samples were collected for the assessment of serum creatinine, renal histopathology, mitochondrial ultrastructure, oxidative stress markers, kidney injury molecule-1 (Kim-1), short-chain fatty acids (SCFAs), and uremic toxins. In human proximal tubular epithelial cells (HK-2 cells), the effects of licorice on cell viability, oxidative stress, inflammatory markers, and mitochondrial membrane potential (MMP) were further investigated. Results: Licorice significantly attenuated VAN-induced nephrotoxicity and restored glutathione peroxidase (GSH-Px) activity while reducing malondialdehyde (MDA) levels. In addition, licorice markedly ameliorated VAN-induced renal histopathological injury, as demonstrated by hematoxylin and eosin staining and transmission electron microscopy. Licorice also reversed VAN-induced intestinal microbiota dysbiosis and increased the relative abundance of SCFA-producing bacteria, including Bacteroides. Moreover, licorice treatment increased fecal SCFA contents and modulated multiple uremic toxins in both serum and renal tissue. Consistently, licorice protected HK-2 cells against VAN-induced cytotoxicity by regulating GSH, interleukin-1\u03b2 (IL-1\u03b2), interleukin-6 (IL-6), tumor necrosis factor-\u03b1 (TNF-\u03b1), and MMP. Conclusions: These findings demonstrate that licorice exerts protective effects against VAN-induced nephrotoxicity in vivo and in vitro, suggesting the potential involvement of oxidative stress, mitochondrial structure and function, inflammation, intestinal microbiota-SCFAs and uremic toxins.<\/jats:p>","DOI":"10.3390\/ph19050728","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:01:30Z","timestamp":1777975290000},"page":"728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protective Effects of Licorice (Glycyrrhiza uralensis) Against Vancomycin-Induced Nephrotoxicity In Vivo and In Vitro"],"prefix":"10.3390","volume":"19","author":[{"given":"Jianping","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China"},{"name":"Engineering Research Center of Prevention and Control for Clinical Medication Risk, Lanzhou 730000, China"},{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China"},{"name":"Engineering Research Center of Prevention and Control for Clinical Medication Risk, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruirui","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China"},{"name":"Engineering Research Center of Prevention and Control for Clinical Medication Risk, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China"},{"name":"Engineering Research Center of Prevention and Control for Clinical Medication Risk, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijia","family":"Wang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhan","family":"Rao","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0371-0361","authenticated-orcid":false,"given":"Xinan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China"},{"name":"Engineering Research Center of Prevention and Control for Clinical Medication Risk, Lanzhou 730000, China"},{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1002\/phar.2388","article-title":"Vancomycin-Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention","volume":"40","author":"Pais","year":"2020","journal-title":"Pharmacotherapy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1093\/cid\/ciz460","article-title":"The Emperor\u2019s New Clothes: Prospective Observational Evaluation of the Association Between Initial Vancomycin Exposure and Failure Rates Among Adult Hospitalized Patients with Methicillin-resistant Staphylococcus aureus Bloodstream Infections (PROVIDE)","volume":"70","author":"Lodise","year":"2020","journal-title":"Clin. 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