〔Abstract〕 To study the effect of metformin sensitizing pancreatic cancer cells with radiotherapy , with a focus on elucidating the underlying mechanisms of radiotherapy resistance . In particular , the role of the PERK/P- eIF2/ATF4 signaling pathway in mediating these effects was preliminarily explored . Methods Pancreatic cancer cell lines (PANC-1 and PANC-2) were categorized into control , radiotherapy , and drug treatment groups . Follow-NF-κB p65 , IκBα, p-NF-κB p65 , p-IκBαprotein expression . Results Compared with the control group , mice in the model group exhibited significant reductions in body weight , elevated DAI scores , shortened small intestinal length , increased histopathological scores , marked downregulation of ZO-1 and Occludin expression , and elevated levels of inflammatory cytokines TNF-αand IL-6 . Additionally , protein expression levels of TLR4 , MyD88 , p-NF- κB p65 , and p-IκBαwere significantly upregulated ( all P < 0. 01) . In contrast , mice in ATPS-treated groups showed dose-dependent improvements , attenuated weight loss , reduced DAI scores , restored intestinal length , de- creased histopathological scores , upregulated ZO-1 and Occludin expression , reduced TNF-αand IL-6 levels , and downregulated TLR4 , MyD88 , p-NF-κB p65 , and p-IκBαprotein expression (all P < 0. 01) . Conclusion ATPS alleviates 5-FU-induced CIM by inhibiting the TLR4/MyD88/NF-κB signaling pathway.