Biochemical and biophysical research communications · 2026
Multi-omic profiling reveals SMAD4 drives linoleic acid-arachidonic acid metabolism to mediate PDAC radiosensitivity via the SLC27A3/FADS2 axis.
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Wang Yang, Zhang Shan, Song Yiran, An Liwei, Zhao Zhangting, Zhou Yingqun, Wang Feng
Аннотация
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.
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.