Identification of Fibrinogen C Domain-Containing protein 1 (FIBCD1) as a novel target for treatment of Post-Traumatic stress disorder (PTSD) and discovery of a novel FIBCD1 inhibitor.

Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition triggered by exposure to traumatic events. Novel therapeutic approaches, including immunotherapy, are being explored to improve treatment. FIBCD1 (Fibrinogen C domain-containing protein 1), expressed in both peripheral tissues and brain glial cells, is implicated in immune regulation. However, its specific role in neuroinflammation and PTSD remains poorly understood. In this study, we used the modified single prolonged stress (mSPS) model to induce PTSD-like phenotypes in mice. Our findings revealed a significant upregulation of FIBCD1 in amygdala microglia after mSPS. Knockdown of FIBCD1 in the amygdala, achieved via adeno-associated virus injection, ameliorated PTSD-related behavior. Mechanistically, FIBCD1 knockdown suppressed neuroinflammation by inhibiting the TLR2/NF-κB signaling pathway. Consistently, in LPS-stimulated BV-2 microglial cells, FIBCD1 knockdown markedly reduced the expression of iNOS, IL-6, and IL-1β. Through virtual screening, we identified a small-molecule inhibitor of FIBCD1, S720-2261, and experimentally validated its binding and inhibitory activity. Administration of S720-2261 in vivo significantly attenuated mSPS-induced PTSD-like behaviors. Further in vitro assays demonstrated that S720-2261 can cross the blood-brain barrier and exhibits anti-inflammatory properties. Collectively, our results indicate that FIBCD1 modulation alleviates PTSD-like symptoms by regulating neuroinflammation and, for the first time, identify S720-2261 as a small-molecule inhibitor targeting FIBCD1.