SARM1 deficiency promotes depressive-like behavior and neuroinflammation through JNK/STING/TBK1 signaling

Neuroinflammation is increasingly recognized as a critical factor in the pathogenesis of depression. SARM1, a dual-function enzyme involved in immune responses and neuronal degeneration, has been implicated in neurodegenerative conditions. However, its role in depression-related neuroinflammation remains unclear. This study investigated the association between SARM1 deficiency and depressive symptoms, elucidating the underlying inflammatory mechanisms. Using SARM1 knockout (KO) mice, we found that SARM1 deficiency induces depressive symptoms, including anhedonia and behavioral despair, as well as selective synaptic impairment characterized by a decline in PSD95 and mature BDNF levels in the reduced hippocampal tissue of SARM1 KO mice. Concurrently, these mice displayed increased phosphorylation of JNK, ERK, p38, and NF-κB, elevated NLRP3 and HO-1 expression, reduced SOD2, and a marked activation of the cGAS-STING-TBK1 pathway in the hippocampus. Similar inflammatory changes and cGAS-STING-TBK1 upregulation were observed in SARM1 KD HT22 cells and primary neurons. Importantly, treatment of SARM1 KD mice with SP600125 significantly alleviated depressive-like behaviors, reduced hippocampal ROS and IL-1β levels, suppressed p-p38, p-NF-κB, and NLRP3, and unexpectedly downregulated p-STING and p-TBK1, while increasing PSD95 expression. Furthermore, Pharmacological inhibition of JNK with SP600125 in SARM1 knockdown mice effectively alleviated depressive-like behaviors, reduced hippocampal ROS and IL-1β, suppressed p-p38/p-NF-κB/NLRP3, and unexpectedly downregulated p-STING/p-TBK1 while improving PSD95 levels. These findings suggest that SARM1 deficiency drives neuroinflammation and depressive phenotypes through dysregulated JNK/STING/TBK1 signaling, highlighting this pathway as a potential therapeutic target for neuroinflammation-associated depression.