{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:47:38Z","timestamp":1790178458921,"version":"4.1.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Radiation enteritis (RE) is a common complication in patients undergoing abdominal and pelvic radiotherapy. Despite the advancements in radiotherapy, effective treatments remain limited. WGX50, a bioactive compound from Sichuan pepper, has shown anti-inflammatory and antioxidant properties. This study investigates the protective effects of WGX50 on RE, focusing on its potential to reduce radiation-induced damage in the intestine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Network pharmacology and molecular docking were used to identify the molecular targets of WGX50. In vitro, human intestinal epithelial cells (HIEC6) and colon cells (NCM460) were exposed to radiation and treated with WGX50. In vivo, C57BL\/6 mice were administered WGX50 prior to radiation exposure. Various assays, including CCK-8, colony formation, flow cytometry, histopathology, and 16S rRNA sequencing, were performed to evaluate cell proliferation, apoptosis, oxidative stress, intestinal damage, and gut microbiota composition. Tissue transcriptome sequencing was conducted to explore differentially expressed genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In vitro, WGX50 significantly mitigated radiation-induced cell damage, enhanced cell proliferation, and reduced apoptosis at non-toxic concentrations. In vivo, WGX50 treatment preserved intestinal morphology and reduced inflammatory infiltration in irradiated mice. WGX50 also protected goblet cells, maintaining mucin production and epithelial barrier function critical for intestinal homeostasis. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) revealed stable binding of WGX50 to Epidermal Growth Factor Receptor (EGFR), key targets involved in oxidative stress regulation and ferroptosis inhibition. Mechanistically, WGX50 upregulated the EGFR-SLC7A11-GPX4 axis, suppressing ferroptosis and protecting intestinal cells. Additionally, 16S rRNA sequencing showed that WGX50 mitigated radiation-induced gut microbiota dysbiosis, preserving microbial diversity and promoting beneficial bacterial populations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>WGX50 demonstrates potent radioprotective effects by reducing oxidative stress, suppressing ferroptosis, and maintaining intestinal homeostasis, including goblet cell function and gut microbiota composition. These findings support WGX50\u2019s potential as a novel therapeutic agent for the prevention and treatment of radiation enteritis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01375-3","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:24:08Z","timestamp":1759919048000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["WGX50 attenuates radiation enteritis by targeting ferroptosis and redox homeostasis via EGFR"],"prefix":"10.1186","volume":"31","author":[{"given":"Zhijing","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanjun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunqing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqi","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganghua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqing","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"issue":"6","key":"1375_CR1","doi-asserted-by":"publisher","first-page":"285","DOI":"10.14740\/gr1567","volume":"15","author":"M Ahmed","year":"2022","unstructured":"Ahmed M, Ahmed R. Radiation in gastroenterology. Gastroenterol Res. 2022;15(6):285\u201396.","journal-title":"Gastroenterol Res"},{"key":"1375_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodres.2019.108782","author":"RR Cardoso","year":"2020","unstructured":"Cardoso RR, Neto RO, dos Santos D\u2019Almeida CT, do Nascimento TP, Pressete CG, Azevedo L, et al. Kombuchas from green and black teas have different phenolic profile, which impacts their antioxidant capacities, antibacterial and antiproliferative activities. Food Res Int. 2020. https:\/\/doi.org\/10.1016\/j.foodres.2019.108782.","journal-title":"Food Res Int"},{"issue":"11","key":"1375_CR3","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1056\/NEJMra1608986","volume":"377","author":"DE Citrin","year":"2017","unstructured":"Citrin DE. Recent developments in radiotherapy. N Engl J Med. 2017;377(11):1065\u201375.","journal-title":"N Engl J Med"},{"key":"1375_CR4","doi-asserted-by":"publisher","unstructured":"D'Auge TG, Giannini A, Bogani G, Di Dio C, Lagana AS, Di Donato V, et al. Prevention, Screening, Treatment and Follow-Up of Gynecological Cancers: State of Art and Future Perspectives. Clin Experiment Obstetr Gynecology. 2023;50(8). https:\/\/doi.org\/10.31083\/j.ceog5008160.","DOI":"10.31083\/j.ceog5008160"},{"key":"1375_CR5","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2025.2460543","author":"S Deng","year":"2025","unstructured":"Deng S, Cao H, Li T, Wang X, Meng J, Zeng T, et al. Lachnospiraceae-bacterium alleviates ischemia-reperfusion injury in steatotic donor liver by inhibiting ferroptosis via the Foxo3-Alox15 signaling pathway. Gut Microbes. 2025. https:\/\/doi.org\/10.1080\/19490976.2025.2460543.","journal-title":"Gut Microbes"},{"key":"1375_CR6","doi-asserted-by":"publisher","unstructured":"Esmeeta A, Adhikary S, Dharshnaa V, Swarnamughi P, Maqsummiya ZU, Banerjee A, et al. Plant-derived bioactive compounds in colon cancer treatment: An updated review. Biomed Pharmacotherapy. 2022;153. https:\/\/doi.org\/10.1016\/j.biopha.2022.113384.","DOI":"10.1016\/j.biopha.2022.113384"},{"issue":"34","key":"1375_CR7","doi-asserted-by":"publisher","first-page":"11196","DOI":"10.1021\/acs.jpcb.5b03116","volume":"119","author":"H-M Fan","year":"2015","unstructured":"Fan H-M, Gu R-X, Wang Y-J, Pi Y-L, Zhang Y-H, Xu Q, et al. Destabilization of Alzheimer\u2019s A\u03b242 protofibrils with a novel drug candidate wgx-50 by molecular dynamics simulations. J Phys Chem B. 2015;119(34):11196\u2013202.","journal-title":"J Phys Chem B"},{"issue":"11","key":"1375_CR8","doi-asserted-by":"publisher","first-page":"2811","DOI":"10.1021\/acs.jcim.7b00452","volume":"57","author":"S Hou","year":"2017","unstructured":"Hou S, Gu R-X, Wei D-Q. Inhibition of \u03b2-amyloid channels with a drug candidate wgx-50 revealed by molecular dynamics simulations. J Chem Inf Model. 2017;57(11):2811\u201321.","journal-title":"J Chem Inf Model"},{"key":"1375_CR9","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.ijbiomac.2020.02.315","volume":"153","author":"C Hou","year":"2020","unstructured":"Hou C, Chen L, Yang L, Ji X. An insight into anti-inflammatory effects of natural polysaccharides. Int J Biol Macromol. 2020;153:248\u201355.","journal-title":"Int J Biol Macromol"},{"issue":"16","key":"1375_CR10","doi-asserted-by":"publisher","first-page":"7692","DOI":"10.1039\/D3FO01684F","volume":"14","author":"W Huang","year":"2023","unstructured":"Huang W, Chen H, He Q, Xie W, Peng Z, Ma Q, et al. Nobiletin protects against ferroptosis to alleviate sepsis-associated acute liver injury by modulating the gut microbiota. Food Funct. 2023;14(16):7692\u2013704.","journal-title":"Food Funct"},{"key":"1375_CR11","doi-asserted-by":"crossref","unstructured":"Jiang Y, Wang Z, Cao K, Xia L, Wei D, Zhang Y. Montmorillonite-Sodium Alginate Oral Colon-Targeting Microcapsule Design for WGX-50 Encapsulation and Controlled Release in Gastro-Intestinal Tract. J Function Biomat. 2024;15(1).","DOI":"10.3390\/jfb15010003"},{"issue":"8","key":"1375_CR12","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1007\/s13238-020-00789-5","volume":"12","author":"P Koppula","year":"2021","unstructured":"Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11\/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021;12(8):599\u2013620.","journal-title":"Protein Cell"},{"issue":"1","key":"1375_CR13","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1093\/jrr\/rraa111","volume":"62","author":"T Kusumoto","year":"2021","unstructured":"Kusumoto T, Ogawara R, Igawa K, Baba K, Konishi T, Furusawa Y, et al. Scaling parameter of the lethal effect of mammalian cells based on radiation-induced OH radicals: effectiveness of direct action in radiation therapy. J Radiat Res. 2021;62(1):86\u201393.","journal-title":"J Radiat Res"},{"key":"1375_CR14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20174297","author":"C Lee","year":"2019","unstructured":"Lee C, Choi C, Kang HS, Shin S-W, Kim S-Y, Park HC, et al. NOD2 supports crypt survival and epithelial regeneration after radiation-induced injury. Int J Mol Sci. 2019. https:\/\/doi.org\/10.3390\/ijms20174297.","journal-title":"Int J Mol Sci"},{"issue":"10","key":"1375_CR15","first-page":"922","volume":"26","author":"B Lian","year":"2023","unstructured":"Lian B, Yu PF, Yang B, Wang SQ, Li MB, Zhao QC. Management of radiation-induced intestinal injury: from multi-disciplinary team team to holistic integrative management. Zhonghua Wei Chang Wai Ke Za Zhi = Chin J Gastrointest Surg. 2023;26(10):922\u20138.","journal-title":"Zhonghua Wei Chang Wai Ke Za Zhi = Chin J Gastrointest Surg"},{"issue":"4","key":"1375_CR16","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.tcb.2023.07.009","volume":"34","author":"X Liu","year":"2024","unstructured":"Liu X, Zhuang L, Gan B. Disulfidptosis: disulfide stress-induced cell death. Trends Cell Biol. 2024;34(4):327\u201337.","journal-title":"Trends Cell Biol"},{"key":"1375_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2020.153402","author":"Y-Q Liu","year":"2021","unstructured":"Liu Y-Q, Wang X-L, He D-H, Cheng Y-X. Protection against chemotherapy- and radiotherapy-induced side effects: a review based on the mechanisms and therapeutic opportunities of phytochemicals. Phytomedicine. 2021. https:\/\/doi.org\/10.1016\/j.phymed.2020.153402.","journal-title":"Phytomedicine"},{"issue":"6","key":"1375_CR18","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.jviscsurg.2020.08.012","volume":"157","author":"L Loge","year":"2020","unstructured":"Loge L, Florescu C, Alves A, Menahem B. Radiation enteritis: diagnostic and therapeutic issues. J Visc Surg. 2020;157(6):475\u201385.","journal-title":"J Visc Surg"},{"key":"1375_CR19","doi-asserted-by":"publisher","DOI":"10.4251\/wjgo.v13.i5.400","author":"H McCaughan","year":"2021","unstructured":"McCaughan H, Boyle S, McGoran JJ. Update on the management of the gastrointestinal effects of radiation. World J Gastrointest Oncol. 2021. https:\/\/doi.org\/10.4251\/wjgo.v13.i5.400.","journal-title":"World J Gastrointest Oncol"},{"key":"1375_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15122761","author":"YK Monfared","year":"2023","unstructured":"Monfared YK, Heidari P, Klempner SJ, Mahmood U, Parikh AR, Hong TS, et al. DNA damage by radiopharmaceuticals and mechanisms of cellular repair. Pharmaceutics. 2023. https:\/\/doi.org\/10.3390\/pharmaceutics15122761.","journal-title":"Pharmaceutics"},{"key":"1375_CR21","doi-asserted-by":"crossref","unstructured":"Omer NNCdS, Araujo IDd, Cruz GMGd, Rodrigues FG. Therapeutics in Radiation-induced Proctopathy: A Systematic Review. J Coloproctol (Rio de Janeiro). 2022;42(1):85\u201398.","DOI":"10.1055\/s-0041-1742258"},{"key":"1375_CR22","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1146\/annurev-biochem-030222-120000","volume":"93","author":"JM Paggi","year":"2024","unstructured":"Paggi JM, Pandit A, Dror RO. The art and science of molecular docking. Annu Rev Biochem. 2024;93:389\u2013410.","journal-title":"Annu Rev Biochem"},{"key":"1375_CR23","doi-asserted-by":"crossref","unstructured":"Ren B, Kwah MX-Y, Liu C, Ma Z, Shanmugam MK, Ding L, et al. Resveratrol for cancer therapy: Challenges and future perspectives. Cancer Lett. 2021;515:63\u201372.","DOI":"10.1016\/j.canlet.2021.05.001"},{"key":"1375_CR24","doi-asserted-by":"publisher","unstructured":"Shabbir U, Rubab M, Daliri EB-M, Chelliah R, Javed A, Oh D-H. Curcumin, Quercetin, Catechins and Metabolic Diseases: The Role of Gut Microbiota. Nutrients. 2021;13(1). https:\/\/doi.org\/10.3390\/nu13010206.","DOI":"10.3390\/nu13010206"},{"issue":"3","key":"1375_CR25","doi-asserted-by":"publisher","first-page":"859","DOI":"10.3233\/JAD-150963","volume":"50","author":"S Shi","year":"2016","unstructured":"Shi S, Liang D, Bao M, Xie Y, Xu W, Wang L, et al. Gx-50 inhibits neuroinflammation via \u03b17 nAChR activation of the JAK2\/STAT3 and PI3K\/AKT pathways. J Alzheimers Dis. 2016;50(3):859\u201371.","journal-title":"J Alzheimers Dis"},{"key":"1375_CR26","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04715-1","author":"P Tai","year":"2023","unstructured":"Tai P, Chen X, Jia G, Chen G, Gong L, Cheng Y, et al. WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis. J Transl Med. 2023. https:\/\/doi.org\/10.1186\/s12967-023-04715-1.","journal-title":"J Transl Med"},{"issue":"1","key":"1375_CR27","doi-asserted-by":"publisher","first-page":"203","DOI":"10.3233\/JAD-121831","volume":"34","author":"M Tang","year":"2013","unstructured":"Tang M, Wang Z, Zhou Y, Xu W, Li S, Wang L, et al. A novel drug candidate for Alzheimer\u2019s disease treatment: gx-50 derived from Zanthoxylum bungeanum. J Alzheimers Dis. 2013;34(1):203\u201313.","journal-title":"J Alzheimers Dis"},{"issue":"10","key":"1375_CR28","doi-asserted-by":"publisher","first-page":"2954","DOI":"10.1158\/0008-5472.CAN-15-2121","volume":"76","author":"K Tsuchihashi","year":"2016","unstructured":"Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, et al. The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-). Cancer Res. 2016;76(10):2954\u201363.","journal-title":"Cancer Res"},{"key":"1375_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-07327-9","author":"H Wang","year":"2025","unstructured":"Wang H, Fan S, Zhan Y, Xu Y, Du Y, Luo J, et al. Targeting EGFR-binding protein SLC7A11 enhancing antitumor immunity of T cells via inducing MHC-I antigen presentation in nasopharyngeal carcinoma. Cell Death Dis. 2025. https:\/\/doi.org\/10.1038\/s41419-024-07327-9.","journal-title":"Cell Death Dis"},{"key":"1375_CR30","doi-asserted-by":"publisher","unstructured":"Xu L, Liu Ye, Chen X, Zhong H, Wang Y. Ferroptosis in life: To be or not to be. Biomed Pharmacotherapy. 2023;159. https:\/\/doi.org\/10.1016\/j.biopha.2023.114241.","DOI":"10.1016\/j.biopha.2023.114241"},{"issue":"22","key":"1375_CR31","doi-asserted-by":"publisher","first-page":"5890","DOI":"10.1080\/10408398.2022.2025535","volume":"63","author":"D Yuan","year":"2023","unstructured":"Yuan D, Li C, Huang Q, Fu X, Dong H. Current advances in the anti-inflammatory effects and mechanisms of natural polysaccharides. Crit Rev Food Sci Nutr. 2023;63(22):5890\u2013910.","journal-title":"Crit Rev Food Sci Nutr"},{"key":"1375_CR32","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abg6428","author":"K-R Zhang","year":"2021","unstructured":"Zhang K-R, Zhang Y-F, Lei H-M, Tang Y-B, Ma C-S, Lv Q-M, et al. Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer. Sci Transl Med. 2021. https:\/\/doi.org\/10.1126\/scitranslmed.abg6428.","journal-title":"Sci Transl Med"},{"key":"1375_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113235","author":"Z Zhang","year":"2024","unstructured":"Zhang Z, Chen H, Li Q. High-fat diet led to testicular inflammation and ferroptosis via dysbiosis of gut microbes. Int Immunopharmacol. 2024. https:\/\/doi.org\/10.1016\/j.intimp.2024.113235.","journal-title":"Int Immunopharmacol"}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01375-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-025-01375-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01375-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:24:10Z","timestamp":1759919050000},"score":1,"resource":{"primary":{"URL":"https:\/\/molmed.biomedcentral.com\/articles\/10.1186\/s10020-025-01375-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1375"],"URL":"https:\/\/doi.org\/10.1186\/s10020-025-01375-3","relation":{},"ISSN":["1528-3658"],"issn-type":[{"value":"1528-3658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,8]]},"assertion":[{"value":"20 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"We confirm that the research involving animals has been conducted in accordance with the guidelines and standards set forth by the Institutional Animal Care and Use Committee (IACUC) and the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals. All experimental protocols were reviewed and approved by the Ethics Committee of the Third Xiangya Hospital of Central South University (Changsha, China). Efforts were made to minimize animal suffering and to use the minimum number of animals necessary to achieve statistically valid results. The ethical approval documentation for this study is included in the supplementary materials.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"309"}}