Targeting Myeloid FoxO1 Ameliorates Sepsis-induced Intestinal Injury by Modulating Tim4 ⁺ Macrophage Glycolysis

Intestinal injury in sepsis contributes to life-threatening systemic infections, accompanied by disruptions in macrophage abundance and function. Forkhead Box O1 (FoxO1) is a critical transcription factor involved in regulating inflammatory responses; however, its role in sepsis-induced intestinal injury remains unclear. In this study, we found that FoxO1 expression was upregulated in intestinal macrophages of septic mice. To investigate its function, myeloid-specific FoxO1 conditional knockout (FoxO1^M-KO) mice were established. Sepsis-induced intestinal barrier dysfunction and oxidative stress were significantly alleviated in these mice, along with improvements in systemic inflammation. Specifically, FoxO1 deletion increased the proportion of Tim4⁺ resident macrophages in intestinal lamina propria and Peyer's patches (PPs) of septic mice. Mechanistically, FoxO1 interacted with the corepressor Sin3a to restrict Tim4 transcription in macrophages. Functionally, FoxO1 knockdown reduced glycolysis in Tim4⁺ macrophages through MAP4K4 signaling, exerting an anti-inflammatory effect that mitigated intestinal injury. Adoptive transfer of Tim4-knockdown primary macrophages into septic mice reversed the protective effects observed in FoxO1^M-KO mice, underscoring the crucial role of FoxO1-regulated Tim4⁺ macrophages in inflammation. Furthermore, the traditional Chinese medicine Huashi Baidu formula (HSBD) inhibited FoxO1 in Tim4⁺ macrophages and ameliorated septic intestinal injury. In conclusion, this study reveals the immunomodulatory and inflammatory role of myeloid FoxO1, identifying it as a novel regulator and therapeutic target for septic intestinal injury.