Isoliquiritigenin from Licorice Attenuates Metastatic Development of Pancreatic Cancer by Regulation of Selective Autophagy-Mediated Ferroptosis and the Tumor Microenvironment.

Isoliquiritigenin (ISL) is a bioactive chalcone obtained from licorice, the ground root of Glycyrrhiza glabra. We previously identified ISL as a late-phase autophagy inhibitor in pancreatic cancer treatment. This study aimed to further explore the involvement of selective autophagy and tumor immunity in its antineoplastic action. Network pharmacology revealed that ISL would downregulate biological processes associated with pancreatic ductal adenocarcinoma (PDAC) including cell migration, extracellular matrix organization and wound healing. Our experimental findings further confirmed ISL's role in inhibiting the epithelial-mesenchymal transition, a key mechanism involved in these processes. ISL also increased the production of reactive oxygen species in both PANC-1 and MIA PaCa-2 PDAC cells, which was intensified through inhibition of autophagy. Furthermore, ISL downregulated glutathione peroxidase 4 (GPX4) and the system Xc- counter-transporter of cystine SLC3A2, while increasing the expression of nuclear receptor coactivator 4 (NCOA4) and decreasing that of ferritin heavy chain 1 (FTH1), thereby promoting ferritinophagy-activated ferroptosis. Alternatively, ISL could induce mitophagy by facilitating mitochondrial dynamics toward fusion through an increase in Parkin and MFN1 gene expression. ISL also modulated the robust transcriptional stress response associated with autophagy and ferroptosis through regulation of CREB1 and VMP1. In the tumor microenvironment, ISL decreased the number of myeloid-derived suppressor cells (MDSCs) while increasing the number of CD4[Formula: see text] and CD8[Formula: see text] T cells in the spleen, tumor tissues and blood of Pan02-xenografted mice. ISL also impaired M2 polarization of macrophages in tumor tissues. The inhibitory effects of ISL could be attenuated by interferon-[Formula: see text] through STAT1 signaling. These results demonstrate that ISL regulates selective autophagy-mediated ferroptosis associated with modulation of the tumor microenvironment when treating pancreatic cancer.