{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:20:07Z","timestamp":1783426807296,"version":"3.54.6"},"reference-count":20,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Xinjiang Uyghur Autonomous Region Department of Science and Technology","award":["2023TSYCLJ0057"],"award-info":[{"award-number":["2023TSYCLJ0057"]}]},{"name":"Observation and Application of the Therapeutic Effect of Traditional Chinese Medicine Prescriptions from Authentic Medicinal Materials in Xinjiang in the Treatment of Burns and Scalds","award":["2024RC012"],"award-info":[{"award-number":["2024RC012"]}]},{"name":"Treatment of Burns and Scalds and Promotion of Full-Functional Skin Reconstruction Using Traditional Chinese Medicine Prescriptions from Characteristic Plants in Southern Xinjiang","award":["2024ZR-009"],"award-info":[{"award-number":["2024ZR-009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury and remains a widely used model of xenobiotic-induced hepatotoxicity. Oxidative stress, mitochondrial dysfunction, and ferroptosis are key events in APAP-mediated liver damage. In this study, we investigated whether L-menthol pretreatment protects against APAP-induced acute liver injury and explored the underlying mechanisms in vivo and in vitro. Male C57BL\/6 mice were pretreated with L-menthol (100 mg\/kg\/day) for 7 days before APAP challenge (300 mg\/kg). L-menthol markedly attenuated hepatic necrosis, inflammatory infiltration, and hepatocyte injury, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, suppressed IL-1\u03b2, IL-6, and TNF-\u03b1 production, restored hepatic glutathione and superoxide dismutase levels, and decreased malondialdehyde accumulation. Transcriptomic analysis revealed significant enrichment of differentially expressed genes in reactive oxygen species- and ferroptosis-related pathways. In APAP-challenged HepG2 cells, L-menthol improved cell viability, preserved mitochondrial ultrastructure, reduced ferrous iron accumulation, was associated with upregulation of Keap1\/Nrf2\/HO-1\/NQO1 pathway-related proteins, and restored GPX4 expression. Collectively, these findings indicate that L-menthol pretreatment attenuates APAP-induced hepatotoxicity, possibly through enhancement of antioxidant defenses and attenuation of ferroptosis-associated changes, supporting its potential as a preventive hepatoprotective small molecule against xenobiotic-induced liver injury.<\/jats:p>","DOI":"10.3390\/cimb48070655","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:04:47Z","timestamp":1783418687000},"page":"655","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["L-Menthol Attenuates Acetaminophen-Induced Acute Liver Injury Associated with Reduced Oxidative Stress and Ferroptosis-Related Changes"],"prefix":"10.3390","volume":"48","author":[{"given":"Menglong","family":"Xu","sequence":"first","affiliation":[{"name":"State Key Laboratory Incubation Base for Conservation and Utilization of Bio-Resource in the Tarim Basin, Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Tarim University, Alar 843300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2016-1824","authenticated-orcid":false,"given":"Yongchao","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory Incubation Base for Conservation and Utilization of Bio-Resource in the Tarim Basin, Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Tarim University, Alar 843300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory Incubation Base for Conservation and Utilization of Bio-Resource in the Tarim Basin, Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Tarim University, Alar 843300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haocheng","family":"Guan","sequence":"additional","affiliation":[{"name":"State Key Laboratory Incubation Base for Conservation and Utilization of Bio-Resource in the Tarim Basin, Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Tarim University, Alar 843300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tinghui","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Xinjiang Hetian College, Hetian 848000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-9133","authenticated-orcid":false,"given":"Shuwei","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory Incubation Base for Conservation and Utilization of Bio-Resource in the Tarim Basin, Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Tarim University, Alar 843300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.jhep.2017.07.005","article-title":"Acetaminophen (APAP) hepatotoxicity-Isn\u2019t it time for APAP to go away?","volume":"67","author":"Lee","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/cpt.1701","article-title":"Acetaminophen-Induced Liver Damage in Hepatic Steatosis","volume":"107","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Li, X., Lao, R., Lei, J., Chen, Y., Zhou, Q., Wang, T., and Tong, Y. (2023). Natural Products for Acetaminophen-Induced Acute Liver Injury: A Review. Molecules, 28.","DOI":"10.3390\/molecules28237901"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105102","DOI":"10.1016\/j.phrs.2020.105102","article-title":"Current etiological comprehension and therapeutic targets of acetaminophen-induced hepatotoxicity","volume":"161","author":"Chowdhury","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/S0140-6736(24)00693-7","article-title":"Acute liver failure","volume":"404","author":"Maiwall","year":"2024","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100766","DOI":"10.1016\/j.jhepr.2023.100766","article-title":"Downregulation of hepatic METTL3 contributes to APAP-induced liver injury in mice","volume":"5","author":"Liu","year":"2023","journal-title":"JHEP Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.7150\/ijbs.69116","article-title":"Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2","volume":"18","author":"Gao","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00204-021-03211-z","article-title":"Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose","volume":"96","author":"Akakpo","year":"2022","journal-title":"Arch. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7815","DOI":"10.1038\/s41467-022-35565-y","article-title":"Targeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of psoriasis","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rozza, A.L., Meira, D.F.F., Souza, B.A., and Pellizzon, C.H. (2014). The gastroprotective effect of menthol: Involvement of anti-apoptotic, antioxidant and anti-inflammatory activities. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086686"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.3923\/pjbs.2002.1101.1103","article-title":"Menthol Prevents Liver Damage Induced by Paracetamol and CCl4","volume":"5","author":"Janbaz","year":"2002","journal-title":"Pak. J. Biol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Matouk, A.I., El-Daly, M., Habib, H.A., Senousy, S., Naguib, A.H.S., Kasem, A.W., Almalki, W.H., Alzahrani, A., Alshehri, A., and Ahmed, A.F. (2022). Protective effects of menthol against sepsis-induced hepatic injury: Role of mediators of hepatic inflammation, apoptosis, and regeneration. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.952337"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yan, R., Lin, B., Jin, W., Tang, L., Hu, S., and Cai, R. (2023). NRF2, a Superstar of Ferroptosis. Antioxidants, 12.","DOI":"10.20944\/preprints202308.1554.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/s41419-024-07224-1","article-title":"New insights into crosstalk between Nrf2 pathway and ferroptosis in lung disease","volume":"15","author":"Chen","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41419-020-2334-2","article-title":"Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure","volume":"11","author":"Yamada","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1039\/D2FO02716J","article-title":"Kaempferol prevents acetaminophen-induced liver injury by suppressing hepatocyte ferroptosis via Nrf2 pathway activation","volume":"14","author":"Li","year":"2023","journal-title":"Food Funct."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"42887","DOI":"10.1021\/acsami.2c10506","article-title":"Astaxanthin Activated the Nrf2\/HO-1 Pathway to Enhance Autophagy and Inhibit Ferroptosis, Ameliorating Acetaminophen-Induced Liver Injury","volume":"14","author":"Cai","year":"2022","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Khare, P., Mangal, P., Baboota, R.K., Jagtap, S., Kumar, V., Singh, D.P., Boparai, R.K., Sharma, S.S., Khardori, R., and Bhadada, S.K. (2018). Involvement of Glucagon in Preventive Effect of Menthol Against High Fat Diet Induced Obesity in Mice. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01244"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1038\/mi.2016.16","article-title":"Transient receptor potential melastatin 8 ion channel in macrophages modulates colitis through a balance-shift in TNF-alpha and interleukin-10 production","volume":"9","author":"Khalil","year":"2016","journal-title":"Mucosal Immunol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/655\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:47:57Z","timestamp":1783424877000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/655"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":20,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cimb48070655"],"URL":"https:\/\/doi.org\/10.3390\/cimb48070655","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}