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A novel approach to sensitize tumor cells to therapy is the administration of antibiotics that target mitochondrial metabolism. We analyzed the effects of a combination of lenvatinib with the tetracycline\u2010class antibiotics tigecycline and eravacycline in DTC cells with reduced response to lenvatinib and explored the underlying mechanism of action. Cell viability was quantified after treatment with either single agents or combination therapies consisting of lenvatinib with tigecycline or eravacycline. Baseline oxidative metabolism and drug\u2010induced changes in oxygen consumption rate were measured. Three\u2010dimensional spheroid cultures were used to better mimic the in\u00a0vivo tumor milieu. Apoptosis was assessed by caspase\u20103\/7 activity, and expression of apoptosis\u2010related proteins was elucidated by immunoblotting. We found that combining lenvatinib with tigecycline or eravacycline resulted in stronger reductions in 2D and 3D cell viability compared to single\u2010agent treatments in K1 DTC cells, which show limited lenvatinib responsiveness. Both combination therapies markedly impaired mitochondrial respiration, accompanied by down\u2010regulation of anti\u2010apoptotic Bcl\u20102 family members, activation of caspase\u20103\/7, and cleavage of Poly (ADP\u2010ribose) polymerase (PARP), which are hallmarks of apoptosis. Although limited to in\u00a0vitro models and subject to pharmacological limitations, our findings provide a mechanistic proof\u2010of\u2010concept that mitochondria\u2010targeting antibiotics may enhance lenvatinib responsiveness in a DTC cell line.<\/jats:p>","DOI":"10.1002\/ijc.70526","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T11:16:14Z","timestamp":1777720574000},"page":"1974-1989","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combination of Lenvatinib and Antibiotics: A Potential Approach to Enhance Sensitivity in Differentiated Thyroid Cancer"],"prefix":"10.1002","volume":"159","author":[{"given":"Celina","family":"Ablinger","sequence":"first","affiliation":[{"name":"Institute of Pharmacy, Pharmaceutical Biology and Clinical Pharmacy, Paracelsus Medical Private University Salzburg  Salzburg 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