ω-3 PUFAs Attenuate Postoperative Ileus by Modulating Macrophage Polarization via the JAK2/STAT3 Signaling Pathway

Xuan Zhao,1,* Jing Yu,1,* Tianle Zhang,1 Yufei Zhang,1 Liuchuang Zhang,1 Ye Wang,1 Chen Yi,1 Huafeng Pan,2 Haifeng Wang,2 Miaomiao Ge,2 Zhiwei Jiang,2 Gang Wang2 1Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gang Wang, Email [email protected] Zhiwei Jiang, Email [email protected]: This study explored the therapeutic effects and mechanisms of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on postoperative ileus (POI) and their potential in preventing or treating POI.Methods: A murine model of postoperative ileus (POI) and an in vitro macrophage inflammation model were employed. Analyses included the assessment of intestinal injury, motility, inflammatory cytokines, macrophage infiltration, and polarization. RNA sequencing implicated the JAK2/STAT3 pathway, which was validated through immunohistochemistry and Western blot. Subsequent STAT3 knockout and overexpression experiments in macrophages further elucidated the underlying mechanism.Results: ω-3 PUFAs alleviated intestinal damage, restored motility, and reduced local pro-inflammatory cytokine levels in POI mice, along with reduced macrophage infiltration. In vitro, ω-3 PUFAs suppressed M1 polarization. RNA-seq implicated the JAK/STAT pathway, and further experiments confirmed that ω-3 PUFAs markedly suppressed the phosphorylation of JAK2, STAT3, and p65 in both macrophages and ileal tissue. Genetic manipulation of STAT3 established that ω-3 PUFAs attenuate inflammation primarily through modulating macrophage polarization.Conclusion: ω-3 PUFAs alleviate POI by inhibiting the JAK2/STAT3 signaling pathway in macrophages, thereby suppressing their polarization toward the pro-inflammatory M1 phenotype and reducing local intestinal inflammation. These findings indicate that ω-3 PUFAs may be a promising prophylactic or therapeutic agent for POI.Keywords: omega-3 polyunsaturated fatty acids, postoperative ileus, macrophage polarization, inflammatory cytokines, JAK2/STAT3 signaling pathway