Kalkan, Omer FarukErdem, SenizErdem, MehmetKalkan, Satinur AteserSahin, ZaferUzun, Ali YavuzKarahan, Suleyman Caner2026-06-192026-06-1920260143-41791532-2785https://doi.org/10.1016/j.npep.2025.102580https://hdl.handle.net/20.500.12899/5766Background: 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.eninfo:eu-repo/semantics/closedAccessNeuroinflammationKisspeptin-10Nlrp3 InflammasomeBcl-2-Associated Athanogene 3PyroptosisAutophagyMicrogliaArticle10.1016/j.npep.2025.102580115413805322-s2.0-105024233051Q2WOS:001639672700001Q3