5-Lipoxygenase triggers depressive-like behaviors via activating NLRP3-induced pyroptosis in CUMS-exposed mice.

5-Lipoxygenase (5-LOX) is implicated the pathogenesis of depression, yet the underlying molecular mechanism remains unclear. In our study, we investigated the dynamic changes of 5-LOX expression after chronic unpredictable mild stress (CUMS) stimulation. The results demonstrated that 5-LOX expression was significantly upregulated in the prefrontal cortex (PFC) after CUMS stimulation for 2 weeks, 4 weeks and 8 weeks. CUMS stimulation activated 5-LOX on neurons, and induced neuronal loss in the PFC. Moreover, the expression levels of pyroptosis-related proteins showed a gradual increase with prolongation of CUMS stimulation. Notably, inhibiting 5-LOX with zileuton effectively alleviated depressive-like behaviors, increased the expression of monoamine neurotransmitters and exerted neuroprotective effects in CUMS-exposed mice. 5-LOX inhibition also markedly reduced the expression levels of pyroptosis-related proteins. We further explored the role of 5-LOX in NLRP3-mediated cell pyroptosis in vitro. 5-LOX knockdown significantly suppressed LPS/ATP-induced pyroptosis in PC12 cells. 5-LOX overexpression enhanced the pyroptosis induced by LPS/ATP, while NLRP3 inhibitors reversed the aggravation. These findings indicate that 5-LOX contributes to the pathogenesis of depression via promoting NLRP3-mediated cell pyroptosis. Thus, 5-LOX inhibition could be applied as a clinic intervention for the treatment of depression.