{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:12:35Z","timestamp":1788952355869,"version":"build-2803163510"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT","doi-asserted-by":"publisher","award":["2022M3A9E4084134"],"award-info":[{"award-number":["2022M3A9E4084134"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2022M3A9E4084134"],"award-info":[{"award-number":["2022M3A9E4084134"]}],"id":[{"id":"https:\/\/ror.org\/01wpjm123","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Reflux esophagitis (RE) is a chronic inflammatory disorder caused by reflux of gastric contents into the esophagus, leading to mucosal injury and epithelial barrier dysfunction. Although proton pump inhibitors are widely used, persistent inflammation and oxidative stress remain important therapeutic challenges. Yeokwisan (YWS) is prescribed for gastroesophageal reflux disease and functional dyspepsia; however, its protective mechanisms against RE remain unclear. This study investigated the protective and anti-inflammatory effects of YWS. Methods: We integrated network pharmacology analysis, mechanistic studies in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, and efficacy evaluation in a rat model of acute RE induced by pyloric and forestomach ligation. Results: Network pharmacology identified 174 common targets between YWS and RE and 23 hub genes through protein\u2013protein interaction network and topological analyses, implicating PI3K\/Akt, MAPK, Ras, HIF-1, chemokine, and other inflammation-related signaling pathways. In LPS-stimulated RAW264.7 macrophages, YWS significantly reduced intracellular reactive oxygen species, nitric oxide, TNF-\u03b1, and IL-6 production without inducing cytotoxicity and suppressed MAPK, PI3K\/Akt, and NF-\u03baB activation. In vivo, YWS attenuated acute reflux-induced esophageal mucosal injury and histopathological alterations, restored esophageal superoxide dismutase activity, reduced malondialdehyde levels, and lowered serum TNF-\u03b1, IL-6, and IL-1\u03b2 levels. YWS also suppressed NF-\u03baB\/I\u03baB activation and COX-2 expression in esophageal tissue. Conclusions: YWS exerted protective effects against acute reflux-induced esophageal injury and anti-inflammatory effects in activated macrophages, accompanied by attenuation of oxidative stress and inflammation-associated signaling. These findings support further investigation of YWS for reflux-associated esophageal inflammation.<\/jats:p>","DOI":"10.3390\/ph19091422","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:19:16Z","timestamp":1788949156000},"page":"1422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Yeokwisan Attenuates Reflux-Induced Esophageal Injury and Suppresses Macrophage Inflammatory Responses Associated with MAPK\/PI3K-Akt and NF-\u03baB\/COX-2 Signaling"],"prefix":"10.3390","volume":"19","author":[{"given":"Kyuhyung","family":"Jo","sequence":"first","affiliation":[{"name":"Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6832-2766","authenticated-orcid":false,"given":"Aejin","family":"Kim","sequence":"additional","affiliation":[{"name":"Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"},{"name":"Korean Convergence Medical Science Major, Campus of Korea Institute of Oriental Medicine, University of Science & Technology, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"So Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Korean Medicine Science Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1711-0906","authenticated-orcid":false,"given":"Dong-Seon","family":"Kim","sequence":"additional","affiliation":[{"name":"Korean Convergence Medical Science Major, Campus of Korea Institute of Oriental Medicine, University of Science & Technology, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"},{"name":"Korean Medicine Science Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7610-9887","authenticated-orcid":false,"given":"Chan-Sik","family":"Kim","sequence":"additional","affiliation":[{"name":"Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"},{"name":"Korean Convergence Medical Science Major, Campus of Korea Institute of Oriental Medicine, University of Science & Technology, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Eunjung","family":"Son","sequence":"additional","affiliation":[{"name":"Korean Medicine Science Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Yun Mi","family":"Lee","sequence":"additional","affiliation":[{"name":"Korean Medicine Science Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.31083\/ph.2021.01003","article-title":"Daidzein ameliorates experimental acute reflux esophagitis in rats via regulation of cytokines","volume":"76","author":"Deng","year":"2021","journal-title":"Pharmazie"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8854945","DOI":"10.1155\/2021\/8854945","article-title":"Protective Effects of Inflammation of Curcumae longae Rhizoma 30% EtOH Extract on Acute Reflux Esophagitis 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