{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:47:54Z","timestamp":1785937674941,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Ministry of Education","doi-asserted-by":"publisher","award":["RS-2023-00246500"],"award-info":[{"award-number":["RS-2023-00246500"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Korean government","award":["RS-2024-00453204"],"award-info":[{"award-number":["RS-2024-00453204"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Endometriosis is a chronic inflammatory disorder characterized by the ectopic growth of endometrial-like tissue, leading to pelvic pain and infertility. Although cepharanthine has well-established anti-inflammatory properties, its therapeutic potential and underlying mechanisms in endometriosis remain largely unexplored. In this study, the effects of cepharanthine were evaluated using a surgically induced mouse model and immortalized human endometrial stromal cell models. Cepharanthine treatment significantly reduced the calculated lesion volume, whereas wet lesion weight did not differ significantly between the groups. Cepharanthine was also accompanied by reduced spleen weight and alterations in the CD4+ helper T-cell population in vivo. In immortalized human ovarian endometriotic stromal cells (ihOESCs), cepharanthine significantly decreased cell viability, induced apoptosis, and disrupted cell-cycle progression. Cepharanthine altered autophagy-related signaling, accompanied by increased acidic vesicle-associated signals and accumulation of LC3B-II and p62\/SQSTM1; however, the direction of autophagic flux remains unclear. These changes were associated with elevated reactive oxygen species production, intracellular Ca2+ redistribution, and mitochondrial dysfunction. Collectively, these findings indicate that cepharanthine reduces calculated lesion volume in vivo and alters mitochondrial function, autophagy-related signaling, apoptosis and cell-cycle progression in ihOESCs, supporting its potential as a therapeutic candidate.<\/jats:p>","DOI":"10.3390\/molecules31152722","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:16:29Z","timestamp":1785935789000},"page":"2722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cepharanthine Reduces Endometriosis Lesions and Alters Mitochondrial and Autophagy-Related Signals in Endometriotic Stromal Cells"],"prefix":"10.3390","volume":"31","author":[{"given":"Miji","family":"Kim","sequence":"first","affiliation":[{"name":"Agri-Food Bio Convergence Institute, Gyeongsang National University, Jinju 52725, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonhyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Seung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea"},{"name":"Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1328-0465","authenticated-orcid":false,"given":"Whasun","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2817-5323","authenticated-orcid":false,"given":"Gwonhwa","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunwoo","family":"Park","sequence":"additional","affiliation":[{"name":"Agri-Food Bio Convergence Institute, Gyeongsang National University, Jinju 52725, Republic of Korea"},{"name":"Department of GreenBio Science (BK21), Gyeongsang National University, Jinju 52725, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(04)17403-5","article-title":"Endometriosis","volume":"364","author":"Giudice","year":"2004","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.rbmo.2019.10.007","article-title":"Pathogenesis of endometriosis: Look no further than John Sampson","volume":"40","author":"Yovich","year":"2020","journal-title":"Reprod. BioMed. Online"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dolmans, M.-M., and Donnez, J. (2022). Emerging drug targets for endometriosis. Biomolecules, 12.","DOI":"10.3390\/biom12111654"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.jss.2010.01.007","article-title":"Cepharanthine exerts anti-inflammatory effects via NF-\u03baB inhibition in a LPS-induced rat model of systemic inflammation","volume":"171","author":"Kudo","year":"2011","journal-title":"J. Surg. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Liu, K., Hong, B., Wang, S., Lou, F., You, Y., Hu, R., Shafqat, A., Fan, H., and Tong, Y. (2023). Pharmacological activity of cepharanthine. Molecules, 28.","DOI":"10.3390\/molecules28135019"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1111\/1751-7915.14059","article-title":"Cepharanthine ameliorates dextran sulphate sodium induced colitis through modulating gut microbiota","volume":"15","author":"Wang","year":"2022","journal-title":"Microb. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.bbrc.2015.02.131","article-title":"Cepharanthine induces apoptosis through reactive oxygen species and mitochondrial dysfunction in human non-small-cell lung cancer cells","volume":"460","author":"Hua","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41420-023-01752-z","article-title":"Cepharanthine, a regulator of keap1-Nrf2, inhibits gastric cancer growth through oxidative stress and energy metabolism pathway","volume":"9","author":"Lu","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_9","first-page":"807","article-title":"Induction of cell cycle arrest and apoptosis in myeloma cells by cepharanthine, a biscoclaurine alkaloid","volume":"33","author":"Kikukawa","year":"2008","journal-title":"Int. J. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1159\/000471234","article-title":"Cepharanthine induces autophagy, apoptosis and cell cycle arrest in breast cancer cells","volume":"41","author":"Gao","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"777","DOI":"10.24976\/Discov.Med.202335178.72","article-title":"Cepharanthine Inhibits Doxorubicin-Induced Cellular Senescence by Activating Autophagy via the mTOR Signaling Pathway","volume":"35","author":"Chen","year":"2023","journal-title":"Discov. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3512","DOI":"10.7150\/thno.55241","article-title":"Ovarian hormones-autophagy-immunity axis in menstruation and endometriosis","volume":"11","author":"Shen","year":"2021","journal-title":"Theranostics"},{"key":"ref_13","first-page":"4707","article-title":"Autophagy in endometriosis","volume":"9","author":"Yang","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lin, Y.-K., Li, Y.-Y., Li, Y., Li, D.-J., Wang, X.-L., Wang, L., Yu, M., Zhu, Y.-Z., Cheng, J.-J., and Du, M.-R. (2022). SCM-198 prevents endometriosis by reversing low autophagy of endometrial stromal cell via balancing ER\u03b1 and PR signals. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.858176"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s13273-024-00473-3","article-title":"Pyroptosis, ferroptosis, and autophagy in immune therapy: Perspective for immunotherapy of endometrial cancer","volume":"21","author":"Ren","year":"2025","journal-title":"Mol. Cell. Toxicol."},{"key":"ref_16","first-page":"e3396","article-title":"Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue","volume":"6","author":"Pelch","year":"2012","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1007\/s43032-023-01225-9","article-title":"Establishment of immortalized human Endometriotic stromal cell line from ectopic lesion of a patient with endometriosis","volume":"30","author":"Son","year":"2023","journal-title":"Reprod. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kalaitzopoulos, D.R., Samartzis, N., Kolovos, G.N., Mareti, E., Samartzis, E.P., Eberhard, M., Dinas, K., and Daniilidis, A. (2021). Treatment of endometriosis: A review with comparison of 8 guidelines. BMC Women\u2019s Health, 21.","DOI":"10.1186\/s12905-021-01545-5"},{"key":"ref_19","first-page":"e2022159","article-title":"Dietary supplements for treatment of endometriosis: A review","volume":"93","author":"Bahat","year":"2022","journal-title":"Acta Bio Med. Atenei Parm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6070","DOI":"10.3390\/molecules28166070","article-title":"Cepharanthine exerts antioxidant and anti-inflammatory effects in lipopolysaccharide (LPS)-induced macrophages and DSS-induced colitis mice","volume":"28","author":"Chen","year":"2023","journal-title":"Molecules"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s10753-013-9744-6","article-title":"Cepharanthine attenuates lipopolysaccharide-induced mice mastitis by suppressing the NF-\u03baB signaling pathway","volume":"37","author":"Ershun","year":"2014","journal-title":"Inflammation"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, J., Chen, G., Meng, Z., Wu, Z., Gan, H., Zhu, X., Han, P., Liu, T., Wang, F., and Gu, R. (2022). Bioavailability enhancement of cepharanthine via pulmonary administration in rats and its therapeutic potential for pulmonary fibrosis associated with COVID-19 infection. Molecules, 27.","DOI":"10.3390\/molecules27092745"},{"key":"ref_23","first-page":"e3763","article-title":"Surgical induction of endometriosis in female mice","volume":"10","author":"Maldonado","year":"2020","journal-title":"Bio-Protoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/s41419-023-05978-8","article-title":"Autophagy mediates an amplification loop during ferroptosis","volume":"14","author":"Lee","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.immuni.2016.02.016","article-title":"Macrophages and iron metabolism","volume":"44","author":"Soares","year":"2016","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"152956","DOI":"10.1016\/j.phymed.2019.152956","article-title":"Cepharanthine: An update of its mode of action, pharmacological properties and medical applications","volume":"62","author":"Bailly","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.tiv.2016.03.010","article-title":"Cepharanthine inhibits in vitro VSMC proliferation and migration and vascular inflammatory responses mediated by RAW264. 7","volume":"34","author":"Paudel","year":"2016","journal-title":"Toxicol. In Vitro"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41421-020-0161-3","article-title":"Emerging roles of ATG proteins and membrane lipids in autophagosome formation","volume":"6","author":"Nishimura","year":"2020","journal-title":"Cell Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nature14893","article-title":"The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy","volume":"524","author":"Lazarou","year":"2015","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.febslet.2005.12.048","article-title":"Cepharanthine triggers apoptosis in a human hepatocellular carcinoma cell line (HuH-7) through the activation of JNK1\/2 and the downregulation of Akt","volume":"580","author":"Biswas","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1093\/molehr\/gap069","article-title":"Endometriotic stromal cells lose the ability to regulate cell-survival signaling in endometrial epithelial cells in vitro","volume":"15","author":"Zhang","year":"2009","journal-title":"Mol. Hum. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.2174\/1871520621666210903163407","article-title":"Cepharanthine regulates autophagy via activating the p38 signaling pathway in lung adenocarcinoma cells","volume":"22","author":"Li","year":"2022","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4622","DOI":"10.1242\/jcs.195057","article-title":"Ratiometric analysis of Acridine Orange staining in the study of acidic organelles and autophagy","volume":"129","author":"Thome","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41421-020-0141-7","article-title":"Lysosome biology in autophagy","volume":"6","author":"Yim","year":"2020","journal-title":"Cell. Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"BSR20190459","DOI":"10.1042\/BSR20190459","article-title":"Combining use of Phillyrin and autophagy blocker alleviates laryngeal squamous cell carcinoma via AMPK\/mTOR\/p70S6K signaling","volume":"39","author":"Wang","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2020.1797280","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy","volume":"17","author":"Klionsky","year":"2021","journal-title":"Autophagy"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1186\/s13287-018-1073-0","article-title":"Autophagy induces G0\/G1 arrest and apoptosis in menstrual blood-derived endometrial stem cells via GSK3-beta\/beta-catenin pathway","volume":"9","author":"Du","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_38","first-page":"121","article-title":"The cellular decision between apoptosis and autophagy","volume":"32","author":"Fan","year":"2013","journal-title":"Chin. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s13273-023-00352-3","article-title":"PCSK9 regulates myocardial ischemia-reperfusion injury through parkin\/pink1-mediated autophagy pathway","volume":"20","author":"Huang","year":"2024","journal-title":"Mol. Cell. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1093\/hmg\/7.10.1573","article-title":"Nuclear genes of human complex I of the mitochondrial electron transport chain: State of the art","volume":"7","author":"Smeitink","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13301","DOI":"10.1038\/s41598-018-31489-0","article-title":"Characterization of Mutations in the Mitochondrial Encoded Electron Transport Chain Complexes in Acute Myeloid Leukemia","volume":"8","author":"Wu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1089\/ars.2013.5777","article-title":"Calcium signaling alterations, oxidative stress, and autophagy in aging","volume":"21","author":"Ureshino","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ceca.2017.08.005","article-title":"The regulation of autophagy by calcium signals: Do we have a consensus?","volume":"70","author":"Bootman","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_44","first-page":"93","article-title":"Biscoclaurine alkaloid cepharanthine protects DNA in TK6 lymphoblastoid cells from constitutive oxidative damage","volume":"60","author":"Halicka","year":"2008","journal-title":"Pharmacol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/0006-2952(90)90271-L","article-title":"Inhibition of active oxygen generation in guinea-pig neutrophils by biscoclaurine alkaloids","volume":"39","author":"Matsuno","year":"1990","journal-title":"Biochem. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kapoor, R., Stratopoulou, C.A., and Dolmans, M.M. (2021). Pathogenesis of Endometriosis: New Insights into Prospective Therapies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111700"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11700","DOI":"10.3892\/ol.2021.12886","article-title":"Association between cellular immune response and spleen weight in mice with hepatocellular carcinoma","volume":"22","author":"Jiang","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1016\/j.fertnstert.2011.02.019","article-title":"T helper (Th)1, Th2, and Th17 interleukin pathways in infertile patients with minimal\/mild endometriosis","volume":"95","author":"Andreoli","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1111\/aji.12426","article-title":"Simultaneous Detection and Evaluation of Four Subsets of CD4+ T Lymphocyte in Lesions and Peripheral Blood in Endometriosis","volume":"74","author":"Takamura","year":"2015","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s10753-013-9734-8","article-title":"Cepharanthine, an alkaloid from Stephania cepharantha Hayata, inhibits the inflammatory response in the RAW264.7 cell and mouse models","volume":"37","author":"Huang","year":"2014","journal-title":"Inflammation"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jnutbio.2018.09.024","article-title":"Quercetin inhibits proliferation of endometriosis regulating cyclin D1 and its target microRNAs in vitro and in vivo","volume":"63","author":"Park","year":"2019","journal-title":"J. Nutr. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e12842","DOI":"10.1111\/jpi.12842","article-title":"Melatonin inhibits endometriosis development by disrupting mitochondrial function and regulating tiRNAs","volume":"74","author":"Park","year":"2023","journal-title":"J. Pineal. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1007\/s43440-024-00625-1","article-title":"Therapeutic effects of S-allyl-L-cysteine in a mouse endometriosis model and its immunomodulatory effects via regulation of T cell subsets and cytokine expression","volume":"76","author":"Park","year":"2024","journal-title":"Pharmacol. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"117186","DOI":"10.1016\/j.taap.2024.117186","article-title":"Toxic effects of dibutyl phthalate on trophoblast through mitochondria mediated cellular dysfunction","volume":"495","author":"Jang","year":"2025","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1007\/s43032-025-01866-y","article-title":"Carvacrol Shows Potential as a Treatment for Endometriosis with Inflammatory Reaction and Antioxidant Properties, Demonstrated in both In Vivo and In Vitro Studies","volume":"32","author":"Jang","year":"2025","journal-title":"Reprod. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"155469","DOI":"10.1016\/j.phymed.2024.155469","article-title":"Therapeutic efficacy and anti-inflammatory mechanism of baicalein on endometriosis progression in patient-derived cell line and mouse model","volume":"130","author":"Park","year":"2024","journal-title":"Phytomedicine"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2722\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:16:44Z","timestamp":1785935804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":56,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31152722"],"URL":"https:\/\/doi.org\/10.3390\/molecules31152722","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]}}}