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The current chemotherapy treatment shows limited efficacy in disseminating metastasis, and its recurrent use is associated with high systemic toxicity. Moreover, the absence of effective therapeutic strategies along with low complexity models for drug screen analysis hinders therapeutic progress. Herein, by developing a three-dimensional (3D) OS model, we found that compared to two-dimensional (2D) OS culture, the 3D spheroid model exhibited upregulation of pro-tumorigenic genes (IL6, OPN, and MMP2), as well as 3D-exclusive activation of TGF-\u03b21 and p-ERK1\/2. Additionally, we report the anticancer potential of robinetin, which successfully suppressed pro-tumorigenic genes and downregulated TGF-\u03b21 and p-ERK1\/2, demonstrating antitumor efficacy at a similar magnitude as doxorubicin while exhibiting low toxicity toward a healthy mesenchymal 3D system. In a scaffold-based 3D model with bone-mimicking stiffness, robinetin treatment suppressed pro-tumorigenic genes related to tumor invasiveness (FN1, OPN, IL6, and MMP2) and decreased the viability of OS cells upon exposure to TGF-\u03b21. This study highlights robinetin as a promising candidate for selective OS therapy while emphasizing the reliability of advanced 3D OS models for anticancer drug screening and translational research.<\/jats:p>","DOI":"10.1021\/acsbiomaterials.6c00437","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:56:37Z","timestamp":1784652997000},"page":"4478-4492","source":"Crossref","is-referenced-by-count":0,"title":["Robinetin Modulates TGF-\u03b2\/ERK Signaling and Tumor-Associated Phenotype in 3D Osteosarcoma Spheroids"],"prefix":"10.1021","volume":"12","author":[{"given":"Isabela","family":"Santos","sequence":"first","affiliation":[{"name":"Harvard Medical School , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"University of Porto , , Rua de Jorge Viterbo Ferreira 228 , ,","place":["Porto, Portugal, 4050-313"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seokgyu","family":"Han","sequence":"additional","affiliation":[{"name":"Harvard Medical School , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6158-3334","authenticated-orcid":true,"given":"Omar Gabriel","family":"Hern\u00e1ndez Zapata","sequence":"additional","affiliation":[{"name":"Harvard Medical School , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Tecnol\u00f3gico de Monterrey , , Tlalpan , ,","place":["Mexico City, M\u00e9xico, 14380"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany Alejandra Garibay","family":"Corral","sequence":"additional","affiliation":[{"name":"Harvard Medical School , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"Tecnol\u00f3gico de Monterrey , , , ,","place":["Chihuahua, Chihuahua, M\u00e9xico, 31150"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Harvard Medical School , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4587-2470","authenticated-orcid":true,"given":"Francisco","family":"Concei\u00e7\u00e3o","sequence":"additional","affiliation":[{"name":"Harvard Medical School , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]},{"name":"University of Twente , , , ,","place":["Enschede, NB, the Netherlands, 7522"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Miguel P. Ferreira de","family":"Oliveira","sequence":"additional","affiliation":[{"name":"University of Porto , , Rua de Jorge Viterbo Ferreira 228 , ,","place":["Porto, Portugal, 4050-313"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6424-0976","authenticated-orcid":true,"given":"Eduarda","family":"Fernandes","sequence":"additional","affiliation":[{"name":"University of Porto , , Rua de Jorge Viterbo Ferreira 228 , ,","place":["Porto, Portugal, 4050-313"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0864-6482","authenticated-orcid":true,"given":"Su Ryon","family":"Shin","sequence":"additional","affiliation":[{"name":"Harvard Medical School , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"2026081717154934400_cit1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.871076","article-title":"Effects of microenvironment in osteosarcoma on chemoresistance and the promise of immunotherapy as an osteosarcoma therapeutic modality","volume":"13","author":"Yu","year":"2022","journal-title":"Front. 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