{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T12:21:35Z","timestamp":1782822095225,"version":"3.54.5"},"reference-count":19,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) grant funded by the Korean Government","award":["RS-2023-00252042"],"award-info":[{"award-number":["RS-2023-00252042"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Cancer therapies frequently induce hepatotoxicity, complicating treatment courses and outcomes. Natural products, including polyphenol-rich extracts, have shown hepatoprotective activity via anti-oxidative and anti-inflammatory mechanisms, often linked to NF-\u03baB and PI3K\u2013Akt pathways. Apple-derived polyphenols (e.g., phlorizin\/phloretin) also demonstrate liver-protective effects in experimental settings. In this study, we examined whether ASE mitigates cancer-related liver damage by rebalancing the apoptosis\u2013survival axis and maintaining PI3K-Akt signaling in an endometrial cancer mouse model. Female Institute of Cancer Research mice with induced endometrial cancer received ASE (0\u2013200 mg) over 13 days; liver tissues were analyzed for Caspase-3, p53, LC3, and SQSTM1 using histology stains, Western blot (e.g., Caspase-3\/9, Bcl-xL, PI3K, Akt, PCNA, IGF-IR), ELISA, and qRT-PCR (GAPDH). ImageJ (version 1.54f; RRID: SCR_003070) quantification statistical analysis followed (mean \u00b1 SD; post-hoc tests). ASE exhibited dose-dependent modulation of apoptosis and survival readouts in liver tissue of cancer-bearing mice: (i) Caspase-9\/3 and Bcl-xL showed differential regulation across doses; (ii) PI3K\u2013Akt and IL-2 signals were preserved or restored toward baseline at specific doses; and (iii) histology indicated partial structural recovery. Thus, ASE may mitigate liver injury by re-balancing apoptosis\u2013survival signaling and promoting structural recovery. Our interpretation emphasizes that dose, route, and formulation are critical for translational potential.<\/jats:p>","DOI":"10.3390\/cimb48010055","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T12:23:44Z","timestamp":1767356624000},"page":"55","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Apple Seed Extract in Cancer Treatment: Assessing Its Effects on Liver Damage and Recovery"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9289-3779","authenticated-orcid":false,"given":"Min-Jee","family":"Oh","sequence":"first","affiliation":[{"name":"General Graduate School of Animal Life Convergence Science, Hankyong National University, 327, Jungang-ro, Ansung 17579, Gyeonggi-do, Republic of Korea"},{"name":"Institute of Applied Humanimal Science, Hankyong National University, 327, Jungang-ro, Ansung 17579, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Su","family":"Park","sequence":"additional","affiliation":[{"name":"Research Center for Endangered Species, National Institute of Ecology, 1210, Geumgang-ro, Maseo-myeon, Seocheon-gun 33657, Chungcheongnam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Yeon","family":"Mo","sequence":"additional","affiliation":[{"name":"General Graduate School of Animal Life Convergence Science, Hankyong National University, 327, Jungang-ro, Ansung 17579, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0996-6912","authenticated-orcid":false,"given":"Sang-Hwan","family":"Kim","sequence":"additional","affiliation":[{"name":"General Graduate School of Animal Life Convergence Science, Hankyong National University, 327, Jungang-ro, Ansung 17579, Gyeonggi-do, Republic of Korea"},{"name":"Institute of Applied Humanimal Science, Hankyong National University, 327, Jungang-ro, Ansung 17579, Gyeonggi-do, Republic of Korea"},{"name":"School of Animal Life Convergence Science, Hankyong National University, 327, Jungang-ro, Ansung 17579, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1634\/theoncologist.6-2-162","article-title":"Hepatotoxicity of chemotherapy","volume":"6","author":"King","year":"2001","journal-title":"Oncologist"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Elbaset, M.A., Afifi, S.M., Esatbeyoglu, T., Abdelrahman, S.S., and Saleh, D.O. (2023). Neuroprotective effects of trimetazidine against cisplatin-induced peripheral neuropathy: Involvement of AMPK-mediated PI3K\/mTOR, Nrf2, and NF-\u03baB signaling axes. Nutrients, 15.","DOI":"10.1155\/2024\/6612009"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.bbrc.2022.01.032","article-title":"Amygdalin protects against acetaminophen-induced acute liver injury by suppressing oxidative stress and inflammation","volume":"624","author":"Zhang","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155100","DOI":"10.1016\/j.phymed.2023.155100","article-title":"Hepatoprotective effects of natural drugs: Current trends, scope, relevance and future perspectives","volume":"121","author":"Datta","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1139\/cjpp-2013-0366","article-title":"Hepatoprotective effects of apple polyphenol extract on aluminum-induced liver oxidative stress in the rat","volume":"92","author":"Cheng","year":"2014","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"106689","DOI":"10.1016\/j.fitote.2025.106689","article-title":"Exploring the hepatoprotective effects of apples: A comprehensive review of bioactive compounds and molecular mechanisms","volume":"185","author":"Pour","year":"2025","journal-title":"Fitoterapia"},{"key":"ref_7","unstructured":"PDQ Integrative, Alternative, and Complementary Therapies Editorial Board (2025, December 16). Laetrile\/Amygdalin (PDQ\u00ae)\u2013Health Professional Version, Available online: https:\/\/www.cancer.gov\/about-cancer\/treatment\/cam\/hp\/laetrile-pdq."},{"key":"ref_8","first-page":"155","article-title":"Amygdalin attenuates acute liver injury induced by LPS\/D-galactosamine in mice","volume":"71","author":"Tang","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_9","first-page":"169","article-title":"The role of TNF\u03b1\/p53 pathway in endometrial cancer mouse model administered with apple seed extract","volume":"37","author":"Kim","year":"2022","journal-title":"Histol. Histopathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/pro.3993","article-title":"The ImageJ ecosystem: Open-source software for image visualization, processing, and analysis","volume":"30","author":"Schroeder","year":"2021","journal-title":"Protein Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/0016-5085(85)90763-2","article-title":"Diffuse hepatic calcification as a sequela to shock liver","volume":"89","author":"Shibuya","year":"1985","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0033-8389(05)70030-0","article-title":"Hepatic calcification","volume":"36","author":"Paley","year":"1998","journal-title":"Radiol. Clin. N. Am."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/modpathol.3800747","article-title":"Cellular and molecular mechanisms of abnormal calcification following ischemia\u2013reperfusion injury in human liver transplantation","volume":"20","author":"Kalantari","year":"2007","journal-title":"Mod. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1053\/jhep.2000.20239","article-title":"Tumor necrosis factor alpha prevents tumor necrosis factor receptor-mediated mouse hepatocyte apoptosis, but not Fas-mediated apoptosis: Role of nuclear factor-\u03baB","volume":"32","author":"Nagaki","year":"2000","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1073\/pnas.94.8.3759","article-title":"Bcl-xL can inhibit apoptosis in cells that have undergone Fas-induced protease activation","volume":"94","author":"Boise","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S0092-8674(00)80450-X","article-title":"Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria","volume":"91","author":"Chandel","year":"1997","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1053\/j.gastro.2004.07.019","article-title":"Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses","volume":"127","author":"Takehara","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"445","DOI":"10.4161\/auto.19496","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy","volume":"8","author":"Klionsky","year":"2012","journal-title":"Autophagy"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Morsy, M.A., Abdel-Latif, R., Abdel Hafez, S.M.N., Kandeel, M., and Abdel-Gaber, S.A. (2023). Paeonol protects against methotrexate hepatotoxicity by repressing oxidative stress, inflammation, and apoptosis\u2014The role of drug efflux transporter. Pharmaceutics, 15.","DOI":"10.3390\/ph15101296"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/1\/55\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T12:50:48Z","timestamp":1767358248000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/1\/55"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,1]]},"references-count":19,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cimb48010055"],"URL":"https:\/\/doi.org\/10.3390\/cimb48010055","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,1]]}}}