Quercetin-Induced Ferroptosis Attenuates Pancreatic Ductal Adenocarcinoma via Facilitating NCOA4-Dependent Ferritinophagy.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of malignancies. Quercetin (QCT), a natural flavonoid, exhibits broad pharmacological activities and minimal toxicity, which makes it a promising candidate for cancer therapy. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic target for cancer treatment. Emerging evidence highlights ferroptosis as a key tumor-suppressive mechanism because it directly kills tumor cells independently of apoptotic effectors and necrosis inducers. The focus of this work is to investigate the significance of QCT in inhibiting PDAC via ferroptosis induction. The antitumor effects of QCT on PDAC were investigated both in vitro, through analyses of cell proliferation and apoptosis, and in vivo by using tumor xenograft models. The in vitro validation results confirmed that QCT inhibited PDAC cell proliferation by modulating ferroptosis via the elevation of intracellular Fe[Formula: see text] and lipid peroxidation. In addition, QCT promoted autophagy by upregulating expression of LC3 and ATG5 autophagy-related proteins. Mechanistically, QCT sensitized PDAC cells to ferroptosis by facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe[Formula: see text] content. Conversely, silencing NCOA4 further supported our mechanistic studies by restoring the downregulated mitochondrial respiration and glycolytic capacity. This study likewise served to demonstrate the significance of NCOA4-mediated ferritinophagy in promoting QCT-regulated tumor cell death. Taken together, our findings reveal the direct protein targets and molecular mechanisms through which QCT enhances antitumor activity, and thus suggest that the targeted induction of ferroptosis via QCT administration may represent a valuable and effective strategy for treating PDAC.