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    Dual role of Kisspeptin-10 in modulating neuroinflammation: Downregulation of NLRP3 inflammasome activation and Caspase-1-mediated pyroptosis, and activation of BAG3-dependent aggrephagy in microglial cells
    (Elsevier, 2026) Kalkan, Omer Faruk; Erdem, Seniz; Erdem, Mehmet; Kalkan, Satinur Ateser; Sahin, Zafer; Uzun, Ali Yavuz; Karahan, Suleyman Caner
    Background: Microglial NLRP3 inflammasome activation plays a central role in the neuroinflammatory cascade that contributes to the pathogenesis of various neurodegenerative diseases. Activation of the canonical inflammasome pathway leads to caspase-1 activation, gasdermin D (GSDMD) cleavage, and pyroptotic cell death, along with the release of pro-inflammatory cytokines such as interleukin-1(3 (IL-1(3) and interleukin-18 (IL-18). Kisspeptin-10 (KP-10), a bioactive neuropeptide of the kisspeptin family, has been shown to exert regulatory effects on immune function; however, its role in neuroinflammation process remains unclear. In this study, we investigated the effects of KP-10 on LPS + ATP-induced NLRP3 inflammasome activation and pyroptotic signaling in murine microglial cells. Results: KP-10 treatment significantly reduced NLRP3 expression, inhibited cleavage of caspase-1 into its active p20 subunit, and decreased GSDMD cleavage into its pore-forming N-terminal fragment (GSDMD-N), indicating suppression of inflammasome-dependent pyroptosis. KP-10 also attenuated the secretion of IL-1(3 and IL-18, confirming functional inhibition of the inflammasome pathway. Mechanistically, KP-10 markedly upregulated Bcl-2-associated athanogene 3 (BAG3), a key co-chaperone involved in selective autophagy. Conclusion: These findings demonstrate that KP-10 suppresses microglial pyroptosis and neuroinflammatory signaling through dual mechanisms: inhibition of the NLRP3-caspase-1-GSDMD axis and activation of BAG3-dependent selective autophagy. This study identifies KP-10 as a novel modulator of microglial inflammasome activity and highlights its therapeutic potential for treating neuroinflammatory and neurodegenerative disorders.
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    The brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone mitigates NLRP3 inflammasome activation and GSDMD-mediated pyroptosis and enhances the negative regulatory pathways of pyroptosis in microglia
    (Elsevier, 2025) Erdem, Mehmet; Erdem, Seniz; Karahan, Suleyman Caner; Alver, Ahmet; Karabulut, Soner; Yildiz, Gokhan
    Microglia are resident immune cells of brain, which serves as a driver of the innate immunity within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that is critical component of the innate immunity and hyperactivation of inflammasome under various conditions contributing to the pathogenesis of neurodegenerative diseases (NDs). 7,8-Dihydroxyflavone (7,8-DHF) have become the focus of attention in studies on NDs due to exert its neurotrophic effects in the CNS. Recent studies have shown encouraging outcomes targeting immune regulatory and neuroprotective properties. 7,8-DHF is a specific tropomyosin-related kinase receptor B (TrkB) agonist and bioavailable brainderived neurotrophic factor (BDNF) mimetic, which has immunomodulator properties in the CNS. In the present study, we researched the effects of BDNF mimetic 7,8-DHF on NLRP3 inflammasome activation, GSDMDmediated pyroptosis, NF-kappa B signaling, ESCRT-III-dependent plasma membrane repair, and selective autophagy in LPS plus ATP-induced murine N9 microglial cells. These findings demonstrated that BDNF mimetic 7,8-DHF significantly reduced NLRP3 inflammasome activation, decreased active caspase-1 the levels, inhibited secretion of proinflammatory cytokine IL-1 beta and IL-18 levels through the I kappa B alpha/NF-kappa B axis. Furthermore, we showed that BDNF mimetic 7,8-DHF activated selective autophagy and ESCRT-III-dependent plasma membrane repair, both of which play crucial roles in the negative regulation of NLRP3 inflammasome activation. Our study reveals that BDNF mimetic 7,8-DHF effectively prevents microglial NLRP3 inflammasome activation and GSDMD-mediated pyroptosis by inhibiting I kappa B alpha/NF-kappa B, promoting ESCRT-III-dependent plasma membrane repair and enhancing selective autophagy.