Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation Blockage

Abstract Intrahepatic cholangiocarcinoma (ICC) is a highly lethal malignancy that currently lacks effective clinical treatments. Eliminating stem cell‐like cancer cells is an extremely promising but challenging strategy for treating ICC. A recently developed synthetic retinoid, sulfarotene, abrogates proliferation, and induces apoptosis of tumor‐repopulating cells (TRCs) that exhibit stem cell‐like properties, yet its effect and underlying mechanisms remain elusive in ICC. It is found that although 5‐fluorouracil, cisplatin, pemigatinib, and gemcitabine all inhibit ICC‐TRCs, sulfarotene demonstrates superior efficacy. Sulfarotene induces retinoic acid receptor alpha (RARɑ) translocation from the cytoplasm to the nucleus, suppressing P‐selectin expression at the transcriptional level. Moreover, it directly interacts with fucosyltransferase 8 (FUT8), inhibiting the core fucosylation of P‐selectin glycoprotein ligand 1 (PSGL1). These actions collectively inhibit ICC‐TRCs via destroying PSGL1‐regulated cytoskeleton. The findings provide a strategy of inhibiting P‐selectin/PSGL1 interaction and altering PSGL1 glycosylation pattern to compromise the cytoskeletal integrity and eliminate ICC‐TRCs.