Pyroptosis　is　an　inflammatory　form　of　programmed　cell　death　that　plays　an　important　role　in　regulating　tumor　progression.　Reniformin　A　(RA)　is　a　natural　compound　isolated　from　the　medicinal　herb　Isodon　excisoides　that　has　been　applied　as　folk　medicine　in　the　treatment　of　esophageal　cancer.　However,　whether　RA　has　an　individual　function　in　cancer　and　the　molecular　mechanisms　remain　unclear.　Here,　we　show　that　in　non-small-cell　lung　cancer　(NSCLC),　RA　inhibits　tumor　growth　by　functioning　as　a　pyroptosis　inducer　to　promote　TLR4/NLRP3/caspase-1/GSDMD　axis.　Specially,　RA　treatment　increased　Toll-like　receptor　4　(TLR4)　protein　expression　level　by　enhancing　the　TLR4　stability.　Based　on　the　molecular　docking,　we　identified　that　RA　directly　bound　to　TLR4　to　activate　the　NLRP3　inflammasome　and　promote　pyroptosis　in　A549　cells.　Moreover,　TLR4　is　essential　for　RA-induced　pyroptosis,　and　loss　of　TLR4　abolished　RA-induced　pyroptosis　and　further　reduced　the　inhibitory　effect　of　RA　on　NSCLC.　In　vivo　experiments　confirmed　that　RA　inhibited　the　growth　of　lung　tumors　in　mice　by　affecting　pyroptosis　in　a　dose-dependent　manner.　Furthermore,　TLR4　knockdown　abolished　RA-induced　pyroptosis　and　inhibited　the　effect　of　RA　chemotherapy　in　vivo.　In　conclusion,　we　propose　that　RA　has　a　significant　anticancer　effect　in　NSCLC　by　inducing　TLR4/NLRP3/caspase-1/GSDMD-mediated　pyroptosis,　which　may　provide　a　potential　strategy　for　the　treatment　of　NSCLC.　©　2024　Elsevier　B.V.