{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T07:05:49Z","timestamp":1779692749377,"version":"3.53.1"},"reference-count":56,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hepatoblastoma (HB) is the most common malignant liver tumor in children, yet therapeutic options remain largely confined to conventional chemotherapy. To identify novel therapeutic targets, we performed gene set enrichment analysis on three publicly available HB datasets and found consistent activation of the proteasome pathway, with marked overexpression of the \u03b25 proteolytic subunit encoded by PSMB5. High PSMB5 expression was associated with poor survival in adult hepatocellular carcinoma, highlighting the proteasome as a candidate for therapeutic vulnerability. Targeting the \u03b25 proteolytic subunit with its selective inhibitor carfilzomib in HB patient-derived xenograft (PDX) models resulted in dose-dependent reductions in cell viability, proliferation, and clonogenic growth, accompanied by induction of apoptosis. Importantly, carfilzomib retained efficacy in three-dimensional PDX cultures, underscoring its activity in physiologically relevant tumor models. Bioinformatic analyses revealed that carfilzomib activates apoptosis and reactive oxygen species (ROS) signaling. Validation experiments in HB cells demonstrated increased ROS levels, with ROS induction correlating with drug sensitivity. Notably, pharmacological scavenging of ROS completely abrogated carfilzomib-induced cytotoxicity, establishing oxidative stress as a key mediator of therapeutic response. Together, these findings identify PSMB5 as a therapeutically actionable target in HB and support proteasome inhibition as a promising precision medicine strategy in HB.<\/jats:p>","DOI":"10.3390\/cells15100864","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:42:18Z","timestamp":1779691338000},"page":"864","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteasome Targeting with Carfilzomib Induces Reactive Oxygen Species-Mediated Apoptosis in Hepatoblastoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Elena Johanna","family":"Weigl","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, University Hospital, LMU Munich, Lindwurmstreet 2a, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3478-1136","authenticated-orcid":false,"given":"Salih","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, University Hospital, LMU Munich, Lindwurmstreet 2a, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Hotes","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, University Hospital, LMU Munich, Lindwurmstreet 2a, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Indersie","sequence":"additional","affiliation":[{"name":"XenTech, 91000 Evry, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Branchereau","sequence":"additional","affiliation":[{"name":"Bic\u00eatre Hospital, AP-HP Paris Saclay University, 94270 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4725-5970","authenticated-orcid":false,"given":"Stefano","family":"Cairo","sequence":"additional","affiliation":[{"name":"Champions Oncology, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-2803","authenticated-orcid":false,"given":"Roland","family":"Kappler","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, University Hospital, LMU Munich, Lindwurmstreet 2a, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e623","DOI":"10.1542\/peds.2015-0224","article-title":"Incidence, Trends, and Survival of Children with Embryonal Tumors","volume":"136","author":"Tulla","year":"2015","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.12688\/f1000research.12239.1","article-title":"Hepatoblastoma: Current understanding, recent advances, and controversies","volume":"7","author":"Czauderna","year":"2018","journal-title":"F1000Research"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/S1470-2045(16)30598-8","article-title":"Risk-stratified staging in paediatric hepatoblastoma: A unified analysis from the Children\u2019s Hepatic tumors International Collaboration","volume":"18","author":"Meyers","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/S1470-2045(13)70272-9","article-title":"Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study","volume":"14","author":"Zsiros","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1056\/NEJMoa0810613","article-title":"Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma","volume":"361","author":"Perilongo","year":"2009","journal-title":"N. 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