Neuroinflammation is a critical pathophysiological mechanism of depression. But the sources and processes involved remain unclear. Recent reports suggest that necroptosis with pro-inflammatory properties may facilitate inflammation. Therefore, we investigated the potential role of necroptosis-associated neuroinflammation in depression.

METHODS:

Depression model mice induced by intraperitoneal injection of lipopolysaccharide (LPS) were treated with RIPK1 inhibitor Necrostatin-1 s (Nec-1 s, 6 mg/kg), RIPK3 inhibitor GSK'872 (6 mg/kg) or intracerebroventricular injection of MLKL inhibitor GW806742X (5 μL of 200 μmol/L). Depressive-like behaviors were assessed using sucrose preference test and tail suspension test. Serum inflammatory cytokines were detected by ELISA, while glial biomarkers were determined by western blots. Hematoxylin & eosin and immunohistochemical staining were utilized to identify morphological characteristics of necroptotic cells in the hippocampus and prefrontal cortex. Further, specific molecules involved in necroptotic pathway were measured by immunoblots.

RESULTS:

Mice treated with LPS exhibited depressive-like behaviors, as well as increased inflammatory cytokines, enhanced MLKL phosphorylation, and decreased cleaved Caspase-8 levels in hippocampus. GSK'872 rather than Nec-1 s exhibited significant antidepressant effects. Although necroptosis was present in both the hippocampus and prefrontal cortex, neuroinflammation was mainly manifested in the hippocampus. Additionally, GSK'872 restored the elevated levels of IL-1β, TNF-α, and HMGB1 in the serum and hippocampus of model mice, and simultaneously ameliorated necroptosis. However, neither GSK'872 nor Nec-1 s had sufficient effect on Caspase-8 and microgliosis. Furthermore, intracerebroventricular injection of GW806742X improved depressive-like behavior and neuroinflammation in hippocampus.

CONCLUSION:

This study provides novel evidence that hippocampal RIPK3-MLKL-dependent necroptosis mediates depressive-like behavior induced by inflammatory stress. During this process, necroptosis may facilitate neuroinflammation by promoting the release of HMGB1. Interventions targeting this pathway may help treat depression with an inflammatory phenotype.

2025-07-01·BIOCHEMICAL PHARMACOLOGY

Discovery of a novel BCL-2 inhibitor GW806742X for the treatment of TNBC

Article

作者: Zhang, Xiaoming ; Zhang, Juan ; Huang, Xue ; Zhang, Dongze ; Liu, Wenjun ; Xu, Jia ; Zhang, Guangbo ; Lu, Linlin ; Chen, Li

Triple-negative breast cancer（TNBC） lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), and traditional treatments cannot accurately target TNBC. Anthracycline- and paclitaxel-based chemotherapeutic agents are still the mainstay of treatment for TNBC, but these chemotherapeutic agents have major toxic side effects and are prone to drug resistance during the treatment of TNBC. In this study, we investigated the efficacy and potential mechanisms of action of GW806742X in the treatment of TNBC. We screened a library of 600 FDA-approved small molecule compounds to identify GW806742X, a small molecule that inhibits the viability of triple-negative breast cancer cells. In vitro, GW806742X was found to be cytotoxic to TNBC cells in a dose-dependent manner and to inhibit the growth of MDA-MB-468 tumors in vivo. Mechanistically, we used PharmMapper to predict the possible targets of GW806742X and demonstrated that the small molecule drug could directly bind to BCL-2 by molecular docking simulations and ITC experiments. Western blot analysis demonstrated that GW806742X could reduce BCL-2 protein levels and possibly promote BCL-2 degradation through the lysosomal pathway. Moreover, GW806742X disrupts NF-κB signaling. In conclusion, this study demonstrates that GW806742X can be a potential therapeutic agent for triple-negative breast cancer by targeting BCL-2.

2025-05-01·EXPERIMENTAL CELL RESEARCH

GW806742X can induce mouse MLKL activation by directly promoting MLKL kinase like domain dimerization

Article

作者: Hu, Hong ; Zhu, Xinxin ; Yuan, Feiyang ; Zhang, Yu ; Nan, Ning ; Wang, Huayi

The dimerization of the MLKL kinase-like domain (KLD) is a crucial step for MLKL activation in necroptosis. In 2014, it was discovered that GW806742X can directly bind to the mouse MLKL KLD via surface plasmon resonance (SPR) (Kd = 9.3 μM), inhibiting TNF-induced membrane translocation of MLKL and necroptosis. Consequently, GW806742X is considered a mouse MLKL inhibitor. In this study, we found that GW806742X blocks TNF-induced RIP1-dependent necroptosis but promotes necroptosis triggered by either RIP3 or MLKL self-oligomerization in the FKBPv chemical dimerizer system. In addition, higher doses of GW806742X can directly induce MLKL-dependent necroptosis and promote MLKL oligomerization, as detected by non-reducing Western blot. Through chemical cross-linking assays, we observed that GW806742X induces dimerization of recombinant mouse MLKL KLD proteins. The dimerization of the MLKL KLD is a direct consequence of RIP3 phosphorylation, a crucial step in RIP3-induced MLKL activation and necroptosis. Therefore, GW806742X exerts a dual effect on necroptosis: it inhibits necroptosis, likely by interfering with RIP1 function, while promoting necroptosis by facilitating MLKL activation.

100 项与 GW806742X 相关的药物交易

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