<p>Sepsis-associated encephalopathy (SAE) is one of the common and severe complications of sepsis, but the pathogenesis remains to be clarified. It has been reported that Treml4 was upregulated in myeloid cells of septic mice, and inhibition of Treml4 was protective against sepsis-induced mortality. But the role of Treml4 on SAE remains unclear. Cecal ligation and puncture (CLP) was carried out to establish a murine sepsis model. The hippocampal tissues and blood samples of mice were collected for the detection of inflammatory factors (IL-1β, IL-6, TNF-α), oxidative stress damage (MDA, SOD), and WB analysis. Brain tissues were collected for immunofluorescence staining to localize the Treml4 receptor and assess the activation and polarization of microglia. Learning and memory abilities of mice were detected with the Morris water maze(MWM) test. In vitro experiments were conducted using small interfering RNA (siRNA) technology in LPS-stimulated microglia to explore the potential mechanism of Treml. Treml4 was upregulated in the hippocampus of CLP mice, associated with the activation of Lyn, Syk and ERK. Knockout of Treml4 significantly reversed the phosphorylation of Lyn, Syk, and ERK in the hippocampus, alleviated inflammation and oxidative stress damage, and protected against memory dysfunction caused by sepsis. Similarly, knockdown of Treml4 could inhibit LPS-induced BV-2 cell activation, and the Lyn agonist Tolimidone (CP-26154) could reverse this effect in vitro. Treml4-mediated inflammatory and oxidative stress injury is crucial in the development of sepsis encephalopathy, indicating the potential role of Treml4 as a target for preventing and treating SAE.</p>