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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.