Quercetin and its derivatives from lotus (Nelumbo nucifera) seedpod extract combat radioresistance by suppressing ACSL4

Abstract Radioresistance poses a significant obstacle in cancer treatment. Lotus seedpod extract (LSE) has demonstrated anticancer effects in various cancer cells. However, its potential against radioresistant tumors remains unclear. In this study, we aimed to investigate the effect of LSE on radioresistant breast cancer cells, explore the underlying mechanism, and identify the major constituents responsible for its cytotoxic effect. LSE, extracted using 70% ethanol, exhibited selective cytotoxic effects against radioresistant breast cancer cells compared with their parental cells. Chemical analysis identified quercetin and its derivatives, hyperoside and miquelianin, as the major constituents responsible for these selective effects. Notably, quercetin displayed the most potent cytotoxicity against radioresistant breast cancer cells compared with hyperoside and miquelianin. Further investigation revealed that these compounds inhibited the activation of DNA repair systems, leading to the accumulation of DNA damage and the induction of apoptosis. Importantly, they efficiently suppressed the expression of ACSL4, a factor previously associated with radioresistance. In an in vivo study, quercetin exhibited a significant suppression of tumor growth in radioresistant tumor‐bearing mice. Taken together, our findings highlight the potential of LSE and its major constituents, quercetin and its derivatives, in overcoming radioresistance in breast cancer. This study provides compelling evidence to support the use of LSE as a medicinal source for the future adjunctive therapy to combat radioresistance in breast cancers.