BMAL1 Drives Cisplatin Resistance in Non‐Small Cell Lung Cancer Via Lactate‐ MRP1 Signaling Pathway

Apr 24, 2026Thoracic cancer

BMAL1 may cause cisplatin resistance in non-small cell lung cancer through lactate and drug transport signals

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Abstract

BMAL1 is identified as a key driver of cisplatin resistance in non-small cell lung cancer (NSCLC).

BMAL1 upregulates the multidrug resistance protein MRP1 through pathways associated with metabolic and oxidative stress.
Increased MRP1 expression is linked to HIF-1α-driven glycolysis, which raises lactate levels.
Lactate activates a complex that further enhances MRP1 expression, creating a feedback loop that supports chemoresistance.
Cisplatin and etoposide can induce BMAL1 expression via AKT signaling due to oxidative stress, reinforcing resistance.
Targeting AKT or MRP1 may reverse the resistance mediated by BMAL1.

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Lung cancer, the leading cause of cancer-related mortality, faces significant therapeutic challenges due to chemoresistance. 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-small cell lung cancer (NSCLC) through metabolic and oxidative stress pathways. We demonstrate that BMAL1 upregulates multidrug resistance protein MRP1 via HIF-1α-driven glycolysis, amplifying lactate production. Lactate activates the TAZ/c-Jun/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-reinforcing resistance mechanism. Critically, targeting AKT or MRP1 reverses BMAL1-mediated resistance. These findings reveal BMAL1 as a metabolic orchestrator linking circadian dysfunction to chemoresistance and propose actionable strategies-such as AKT inhibition or chronotherapy-to circumvent therapeutic failure. This work underscores the necessity of targeting circadian-metabolic crosstalk to improve outcomes in NSCLC.

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BMAL1 Drives Cisplatin Resistance in Non‐Small Cell Lung Cancer Via Lactate‐ MRP1 Signaling Pathway

Abstract

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