Kaempferol induces mitochondrial dysfunction and mitophagy by activating the LKB1/AMPK/MFF pathway in breast precancerous lesions.

Kaempferol has been suggested to be an effective anticancer agent in several malignant tumors. However, its function and mechanisms in breast precancerous lesions remain largely elusive. Here, we showed that kaempferol induced excessive mitochondrial fission and mitochondrial damage with activated mitochondrial fission factor (MFF)-mediated dynamin-related protein (DRP) 1 mitochondrial translocation. As a result, the PTEN-induced putative kinase 1 (PINK1)/Parkin signaling pathway was activated, accompanied by excessive mitophagy and reduced mitochondrial mass in cells. We also revealed that kaempferol-induced lethal mitophagy contributed to inhibiting breast precancerous lesion growth in vitro and in vivo. Furthermore, we verified serine/threonine kinase 11 (STK11/LKB1)/AMP-activated protein kinase (AMPK) pathway deficiency in breast precancerous lesions. Moreover, LKB1/AMPK pathway reactivation by kaempferol was required for excessive mitochondrial fission and lethal mitophagy. Taken together, our findings shed new light on the molecular mechanisms related to breast cancer prevention by kaempferol and provide evidence for its potential clinical application.