Multi-omic profiling reveals SMAD4 drives linoleic acid-arachidonic acid metabolism to mediate PDAC radiosensitivity via the SLC27A3/FADS2 axis

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.