doi:10.1038/s41419-024-06492-1engBayona, ClaraAlza, LíaRandelovic, TeodoraSallán, Marta C.Visa, AnnaCantí, CarlesOchoa, IgnacioOliván, SaraHerreros, JuditTetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approachART-2024-136959Glioblastoma (GBM) is a highly malignant brain tumour characterised by limited treatment options and poor prognosis. The tumour microenvironment, particularly the central hypoxic region of the tumour, is known to play a pivotal role in GBM progression. Cells within this region adapt to hypoxia by stabilising transcription factor HIF1-α, which promotes cell proliferation, dedifferentiation and chemoresistance. In this study we sought to examine the effects of NNC-55-0396, a tetralol compound which overactivates the unfolded protein response inducing apoptosis, using the organ-on-chip technology. We identified an increased sensitivity of the hypoxic core of the chip to NNC, which correlates with decreasing levels of HIF1-α in vitro. Moreover, NNC blocks the macroautophagic process that is unleashed by hypoxia as revealed by increased levels of autophagosomal constituent LC3-II and autophagy chaperone p62/SQSTM1. The specific effects of NNC in the hypoxic microenvironment unveil additional anti-cancer abilities of this compound and further support investigations on its use in combined therapies against GBM.2024http://zaguan.unizar.es/record/13158510.1038/s41419-024-06492-1http://zaguan.unizar.es/record/131585oai:zaguan.unizar.es:131585info:eu-repo/grantAgreement/EC/H2020/829010/EU/Advanced and versatile PRInting platform for the next generation of active Microfluidic dEvices/PRIMEThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 829010-PRIMEinfo:eu-repo/grantAgreement/ES/MINECO/DIN2020-011544info:eu-repo/grantAgreement/ES/MINECO/RTI2018-094739-B-I00CELL DEATH & DISEASE 15, 2 (2024), 127 [8 pp.]byhttps://creativecommons.org/licenses/by/4.0/deed.esinfo:eu-repo/semantics/openAccess