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While metabolic reprogramming and circadian disruptions are implicated in tumor progression, their interplay in driving resistance remains unclear. This study identifies BMAL1, a core circadian regulator, as a key driver and potential initiator of cisplatin resistance in non\u2010small cell lung cancer (NSCLC) through metabolic and oxidative stress pathways. We demonstrate that BMAL1 upregulates multidrug resistance protein MRP1 via HIF\u20101\u03b1\u2010driven glycolysis, amplifying lactate production. Lactate activates the TAZ\/c\u2010Jun\/Snail complex to increase MRP1 expression, establishing a feedforward loop that sustains chemoresistance. Furthermore, cisplatin and etoposide induce BMAL1 expression through AKT signaling in response to oxidative stress, creating a self\u2010reinforcing resistance mechanism. Critically, targeting AKT or MRP1 reverses BMAL1\u2010mediated resistance. These findings reveal BMAL1 as a metabolic orchestrator linking circadian dysfunction to chemoresistance and propose actionable strategies\u2014such as AKT inhibition or chronotherapy\u2014to circumvent therapeutic failure. This work underscores the necessity of targeting circadian\u2010metabolic crosstalk to improve outcomes in NSCLC.<\/jats:p>","DOI":"10.1111\/1759-7714.70279","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T13:44:58Z","timestamp":1777038298000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>BMAL1<\/scp>\n                    Drives Cisplatin Resistance in Non\u2010Small Cell Lung Cancer Via Lactate\u2010\n                    <scp>MRP1<\/scp>\n                    Signaling Pathway"],"prefix":"10.1111","volume":"17","author":[{"given":"Zixin","family":"Shi","sequence":"first","affiliation":[{"name":"Research Laboratory of Tumor Microenvironment Wannan Medical University  Wuhu China"},{"name":"School of Anesthesiology, Wannan Medical University  Wuhu 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Wannan Medical University  Wuhu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijun","family":"Wei","sequence":"additional","affiliation":[{"name":"Research Laboratory of Tumor Microenvironment Wannan Medical University  Wuhu China"},{"name":"Anhui Province Key Laboratory of Basic Research and Transformation of Age\u2010Related Diseases Wannan Medical University  Wuhu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8368-5129","authenticated-orcid":false,"given":"Zhihao","family":"Wu","sequence":"additional","affiliation":[{"name":"Research Laboratory of Tumor Microenvironment Wannan Medical University  Wuhu China"},{"name":"Anhui Province Key Laboratory of Basic Research and Transformation of Age\u2010Related Diseases Wannan Medical University  Wuhu China"},{"name":"Anhui Province Key Laboratory of Non\u2010Coding RNA Basic and Clinical Transformation, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases Wannan Medical University  Wuhu 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