{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T06:24:12Z","timestamp":1787293452162,"version":"build-2736575974"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>18\u03b2-Glycyrrhetinic acid (18\u03b2-GA), a major bioactive triterpenoid from licorice, has demonstrated anti-cancer potential; however, its mechanisms against lung adenocarcinoma (LUAD) remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study employed an integrated approach combining network pharmacology, bioinformatics, and experimental validation to investigate the anti-LUAD efficacy and underlying molecular targets of 18\u03b2-GA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      assays demonstrated that 18\u03b2-GA dose-dependently inhibited LUAD cell proliferation, migration, and colony formation, while significantly suppressing tumor growth in a Lewis lung carcinoma (LLC) allograft model. By integrating network pharmacology with TCGA transcriptomic data, MET was identified as a core upstream target, and the PI3K\/AKT signaling pathway was revealed as a significantly enriched pathway. Molecular docking and molecular dynamics simulations revealed that 18\u03b2-GA forms stable, high-affinity complexes in the catalytic pockets of both MET and AKT. Subsequent biological validations confirmed that 18\u03b2-GA attenuated the phosphorylation of critical signaling components, including MET, PI3K, AKT, and mTOR, without altering their mRNA or total protein expression. Crucially, functional rescue assays revealed that exogenous MET activation via its specific ligand HGF simultaneously reversed the 18\u03b2-GA-induced suppression of both p-MET and p-AKT. In contrast, the AKT agonist SC79 effectively restored p-AKT levels and reversed the anti-tumor efficacy of 18\u03b2-GA, but it failed to rescue the inhibition of upstream p-MET. This unidirectional reversal rigorously validates MET as the upstream regulator of AKT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>18\u03b2-GA suppresses LUAD by targeting upstream MET to drive a top-down cascade blockade of the PI3K\/AKT\/mTOR signaling pathway, providing a pharmacological rationale for its application in LUAD targeted therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1752632","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:35:28Z","timestamp":1787290528000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["18\u03b2-glycyrrhetinic acid inhibits lung adenocarcinoma progression by targeting the MET\/AKT signaling axis"],"prefix":"10.3389","volume":"14","author":[{"given":"Gongyu","family":"Wu","sequence":"first","affiliation":[{"name":"School of Pharmacy, Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilin","family":"Guan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Lv","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changjiu","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanzhen","family":"Su","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-0-387-46401-5_1","article-title":"Curcumin: the Indian solid gold","volume":"595","author":"Aggarwal","year":"2007","journal-title":"Adv. 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