Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent SMAD4 inactivation and extensive lipid metabolic rewiring, yet the mechanistic crosstalk between these processes remains poorly elucidated. Methods Multi-omic profiling involving CUT&Tag, transcriptomic, and spatial metabolomic analyses reveals a novel regulatory mechanism of arachidonic acid metabolism governed by SMAD4 that determines PDAC radioresistance. Results Spatial metabolomics revealed that SMAD4 deficiency decreases arachidonic acid metabolism in PDAC tissues. Mechanistically, SMAD4 binds to the promoters of SLC27A3 and FADS2 , facilitating the enrichment of the linoleic acid-arachidonic acid axis. Conversely, SMAD4 deficiency leads to a decrease in the linoleic acid-arachidonic acid axis, which may inhibit ferroptosis and promote radioresistance in PDAC tumors. Conclusions Collectively, our study identifies that SMAD4 acts as a transcriptional activator of SLC27A3 and FADS2 , driving linoleic acid uptake and its conversion to arachidonic acid, which may subsequently trigger ferroptosis and enhance radiosensitivity.