Chao Song, Luting Zhang, Sheng Xu, Xu-An Wang, Xinyi Zhang, Kai Xuan Cheong, Ganggang Wang, Mengmeng Liu, Yazhou Wang, Yifei Zhang, Taochen He, Kai Ding, Yu Chen, Xin Liang, Bing Zhu, Qianzhi Ni, Wenquan Wang, Jingjing Li, Wenhui Lou, Liang Liu
Integrated single-cell transcriptomics and clinical analyses reveal elevated DDR1 expression in pancreatic ductal adenocarcinoma (PDAC) tissues, which correlates with poor prognosis. Mechanistically, collagen-activated Discoidin Domain Receptor 1 (DDR1) recruits SHC1 to activate the MAPK/ERK pathway, thereby driving transcriptional upregulation of SLC40A1 via the ERK-MYC axis. SLC40A1, encoding an iron exporter, reduces intracellular labile iron pools, thereby suppressing lipid peroxidation and ferroptosis. Consequently, DDR1 overexpression confers resistance to dihydroartemisinin (DHA)-induced ferroptosis in PDAC cells, characterized by diminished ROS accumulation, mitochondrial shrinkage, and cristae loss. Conversely, DDR1 knockdown or pharmacological inhibition (Dasatinib) sensitizes PDAC cells to DHA. Crucially, combining Dasatinib and DHA treatment synergistically inhibits tumor growth in vivo by reactivating ferroptosis, as evidenced by increased 4-HNE accumulation and decreased Ki67 expression. These findings identify DDR1 as a key regulator of iron metabolism and ferroptosis in PDAC, suggesting that dual targeting of DDR1 and ferroptosis represents a promising therapeutic strategy.