AbstractSeveral studies have suggested the potential value ofHouttuynia cordataas a therapeutic agent in lung cancer, but direct evidence is still lacking. The study aimed to determine the regulatory impact of a majorH. cordataconstituent derivative (sodium new houttuyfonate [SNH]) on lncRNA networks in non‐small cell lung cancer (NSCLC) to identify new potential therapeutic targets. After exposing NSCLC cells to SNH, we analysed the following: cell death (via flow cytometry, TUNEL and ASC speck formation assays), immune factors (via ELISA), gene transcription (via RT‐qPCR), subcellular localisation (via FISH), gene–gene and gene‐protein interactions (via dual‐luciferase reporter and RNA immunoprecipitation assays, respectively) and protein expression and distribution (via western blotting and immunocytochemistry or immunohistochemistry). In addition, statistical analysis (via one‐way ANOVA or unpairedt‐tests) was performed. Exposure to SNH promoted NSCLC cell pyroptosis, concomitant with significant up‐regulation of TCONS‐14036, a novel lncRNA. Mechanistic research demonstrated that TCONS‐14036 functions as a competing endogenous (ce)RNA by sequestering microRNA (miR)‐1228‐5p, thereby up‐regulating PRKCDBP‐encoding transcript levels. Indeed, PRKCDBP promoted pyroptosis by activating the NLRP3 inflammasome, resulting in CASP1, IL‐1β and GSDMD cleavage. Our findings elucidate the potential molecular mechanisms underlying the ability of SNH to suppress NSCLC growth through activation of pyroptosis via the TCONS‐14036/miR‐1228‐5p/PRKCDBP pathway. Thus, we identify a new potential therapeutic targets for NSCLC.