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To address this, we explored the therapeutic potential of combining epirubicin, an anthracycline commonly associated with the development of resistance in cancer cells and with known cytotoxic effects, with 4\u2010methylumbelliferone, a plant\u2010derived coumarin. Our results demonstrated a coactive enhancement of epirubicin efficacy when this combination was applied to 3D breast cancer models, irrespective of molecular subtype. Mechanistically, 4\u2010methylumbelliferone inhibits synthesis of hyaluronan, a key component of the tumor microenvironment that promotes tumor growth and metastasis. By disrupting hyaluronan production, this compound facilitated drug penetration into tumor spheroids and reduced the expression of drug efflux pumps, thereby increasing intracellular drug accumulation. Consequently, the combined treatment led to a significant reduction in cell viability and promotion of cell death. Our findings suggest that targeting hyaluronan metabolism in conjunction with conventional chemotherapy offers a promising strategy to overcome drug resistance in breast cancer. This drug repositioning approach not only improves treatment efficacy but also highlights the potential of targeting the tumor microenvironment to enhance cancer therapy. Further studies are warranted to elucidate the underlying mechanisms and to evaluate the clinical translation of this combination therapy.<\/jats:p>","DOI":"10.1002\/iub.70075","type":"journal-article","created":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T08:51:15Z","timestamp":1762591875000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["4\u2010Methylumbelliferone Sensitizes Breast Cancer Spheroids to Chemotherapeutic Treatment With Epirubicin: New Perspectives for Pharmacological Repositioning"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-9101","authenticated-orcid":false,"given":"Daiana Luj\u00e1n","family":"Vitale","sequence":"first","affiliation":[{"name":"Laboratorio de Microambiente Tumoral \u2013 Centro de Investigaciones B\u00e1sicas y Aplicadas (CIBA) \u2013 Universidad Nacional del Noroeste de la Provincia de Buenos Aires  Jun\u00edn 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