Fructus Arctii Mitigates Depressive Disorder via the Let‐7e‐Modulated Toll‐Like Receptor (TLR) Signaling Pathway.

Background: Depressive disorder is a common and serious public health challenge globally. Fructus arctii is a traditional medicinal plant ingredient with diverse pharmacological effects. This study aimed to investigate the therapeutic potential of Fructus arctii in alleviating depressive‐like behaviors. Materials and Methods: We established a chronic unpredictable mild stress (CUMS)‐induced depression mouse model to assess the antidepressant effects of Fructus arctii. BV2 cells treated with lipopolysaccharide (LPS) were used to mimic neuronal damage. Behavioral tests, including the sucrose preference test, tail‐suspension test, and forced swim test, were conducted to evaluate the impact of Fructus arctii on depressive‐like behaviors. Let‐7e expression was detected by RT‐qPCR, and TLR4 signaling pathway activation was evaluated by western blot analysis, which also assessed the inflammatory response by measuring levels of IL‐6, IL‐1β, MCP‐1, TNF‐α, and iNOS. Immunohistological analysis was conducted to detect the expression of microglia markers. Luciferase reporter assays verified the interaction between let‐7e and TLR4. Results: Fructus arctii administration effectively alleviated depressive‐like behaviors induced by CUMS in mice, as evidenced by improved sucrose preference and reduced immobility time in behavioral tests. Mechanistically, Fructus arctii reversed the CUMS‐induced downregulation of let‐7e and upregulation of TLR4 and MyD88 protein levels in mice hippocampus tissues. In addition, Fructus arctii suppressed microglial activation and reduced the levels of inflammatory factors by upregulating let‐7e. Let‐7e was verified to bind to TLR4, thereby negatively regulating its expression. TLR4 overexpression reversed the suppressive effect of let‐7e upregulation on inflammatory reactions and microglial activation. Furthermore, intracerebroventricular injection of let‐7e agomiR alleviated depressive‐like behavior and inhibited microglial activation in vivo. Conclusion: In summary, Fructus arctii mitigates depression by regulating the let‐7e/TLR4/MyD88 pathway, offering new insights into potential depression therapies. [ABSTRACT FROM AUTHOR]