Activation of the caspase-1/gasdermin D pathway via α-linolenic acid-mediated GPR120 signaling induces pyroptosis and suppresses ovarian cancer tumor growth

To investigate the role and underlying mechanism of α-linolenic acid (ALA) in ovarian cancer (OC), particularly its relationship with pyroptosis and the GPR120/caspase-1/Gasdermin D (GSDMD) pathway. Human OC cell lines (SKOV3, A2780), THP-1 monocytes, and SKOV3 subcutaneous xenograft models in nude mice were employed. Key assays included cell counting kit-8 (CCK-8) for cell viability, lactate dehydrogenase release for membrane damage detection, ELISA for Interleukin-1β (IL-1β) and IL-18 measurement, Western blot and quantitative polymerase chain reaction (qPCR) for analyzing pyroptosis-related molecules, molecular docking for ALA-GPR120 binding, and flow cytometry. Mice were administered ALA at a dose of 50 mg/kg by intraperitoneal injection, twice weekly for 4 weeks, or saline. ALA induced pyroptosis in OC cells both in vitro and in vivo, accompanied by increased membrane damage, elevated levels of IL-1β and IL-18, and activation of pyroptosis-related molecules. It targeted and inhibited GPR120 to activate the caspase-1/GSDMD pathway, with GSDMD identified as a critical effector. ALA also promoted M1 macrophage polarization and inhibited OC cell activity. In vivo, ALA reduced tumor size, upregulated pyroptosis markers, downregulated GPR120, and caused no significant toxicity. ALA induces OC cell pyroptosis and modulates the tumor microenvironment via the GPR120/caspase-1/GSDMD pathway, safely inhibiting OC growth. This reveals a novel mechanism, supporting ALA as a potential therapeutic candidate for OC, though further research into downstream regulation is required.