{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T01:58:31Z","timestamp":1792979911207,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Chemotherapy remains the frontline treatment strategy for triple\u2010negative breast cancer (TNBC). However, the aggressive nature of TNBC, due to metabolic reprogramming, is often associated with chemoresistance, which limits treatment efficacy. Herein, we investigated the impact of altered lipid homeostasis, in particular, the fatty acid \u03b2\u2010oxidation (FAO) pathway, during doxorubicin (Dox)\u2010induced chemoresistance and its effect on drug retention and efficacy in TNBC cells. Results indicate that Dox\u2010induced chemoresistance in MDA\u2010MB\u2010231 cells and an in vivo Dox\u2010resistance breast cancer model in SCID mice are associated with a marked upregulation of FAO. Intriguingly, the basal levels of carnitine palmitoyltransferase 1 (CPT1; a rate\u2010limiting enzyme of FAO), CD36, (a fatty acid translocase), FAO\u2010related gene transcript levels, and acetyl\u2010CoA production were significantly elevated with increased degree of Dox resistance. These changes were paralleled by enhanced uptake of fatty acids and their oxidation. Dox\u2010resistance in TNBC cells was associated with enhanced mitochondrial respiration, possibly due to increased activities of complex I and IV. Conversely, inhibition of CPT1 by etomoxir caused increased intracellular Dox retention, leading to Dox\u2010induced cytotoxicity and attenuating the invasiveness of TNBC cells. Importantly, FAO\u2010derived ATP levels, compared to glucose\u2010derived ATP, seem to enhance the invasiveness of Dox\u2010resistant cells. Mechanistically, Dox\u2010resistance potentiated FAO via CREB activation, which in turn led to the enhancement of the PGC1\u03b1\/PPAR\u03b1\/CD36\u2010CPT1 axis. Taken together, Dox\u2010resistance reprograms cellular metabolism towards FAO regulatory circuit sustaining the mitochondrial bioenergetics, promoting drug efflux, and accentuating breast cancer progression. Based on these findings, it is possible that FAO inhibitors effectively combat drug\u2010induced TNBC chemoresistance.<\/jats:p>","DOI":"10.1002\/mc.70072","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T06:35:48Z","timestamp":1765866948000},"page":"312-327","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Doxorubicin Resistance Reprograms Triple\u2010Negative Breast Cancer Cell Metabolism via the Fatty Acid \u03b2\u2010Oxidation (FAO)\u2010CD36 Regulatory Circuit: Relevance of Enhanced FAO on Tumor Cell Invasiveness"],"prefix":"10.1002","volume":"65","author":[{"given":"Sunita","family":"Kumari","sequence":"first","affiliation":[{"name":"Department of Applied Biology CSIR\u2010Indian Institute of Chemical Technology Hyderabad India"},{"name":"Academy of Scientific and Innovative Research Ghaziabad 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