Natural Compound Melatonin Suppresses Breast Cancer Development by Regulating Circadian Rhythm

<b>Background:</b> Breast cancer remains a major global health threat to women. While current therapies exist, their limitations necessitate novel strategies. Melatonin, an endogenous circadian regulator, has shown anti-tumor potential, but its mechanisms from a circadian perspective require further exploration. <b>Methods:</b> The anti-tumor effects of melatonin were evaluated through cell proliferation, colony formation, and apoptosis assays. Through data analysis and experimental verification at the RNA and protein levels, the regulatory effect of it on the core clock gene BMAL1 was studied. The role of BMAL1 in mediating melatonin's suppression of glucose metabolism was assessed by measuring glucose uptake and lactate production. Downstream effector molecules of BMAL1 were identified through molecular interaction and transcriptional regulation analyses. <b>Results:</b> Melatonin significantly inhibited breast cancer cell proliferation and colony formation and induced apoptosis. Mechanistically, it upregulates the core clock gene BMAL1, which suppresses glucose metabolism. ALDH3A1 was identified as a key downstream target of BMAL1, defining a novel "melatonin-BMAL1-ALDH3A1" axis. In vivo studies confirmed that this axis effectively inhibits tumor growth without apparent toxicity, and SR8278 also shows a synergistic effect when used in combination with melatonin. <b>Conclusions:</b> Our findings elucidate the role of the "melatonin-BMAL1-ALDH3A1" axis in combating breast cancer, offering a new direction for treatment and laying the groundwork for developing precision chronotherapy-based combination regimens.