Miltirone promotes pyroptosis via increasing pyroptosis-related protein NLRP3 and AIM2 in kidney renal clear cell carcinoma.

BACKGROUND: Pyroptosis, a type of programmed cell death, exerts direct influence on inflammatory processes and immune response. A previous study suggests that miltirone exhibits notable anti-tumor activities and has been shown to induce tumor cell pyroptosis. Nevertheless, the therapeutic value of miltirone in kidney renal clear cell carcinoma (KIRC) remains underexplored. METHODS AND RESULTS: Using TCGA pan-cancer data, we uncovered widely expressed pyroptosis-related genes (NLRP3 and AIM2). Mechanistically, the genomic amplification alteration and high CNV percentages in pan-cancer induced an abnormal expression. StromalScore analysis suggested that NLRP3 and AIM2 were activated by the tumor immune microenvironment in KIRC. Enrichment analysis indicated that NLRP3 and AIM2 regulated the inflammatory response and were related to immune infiltration in KIRC. Furthermore, Kaplan-Meier curve and ROC analysis indicated that a high expression of AIM2 was associated with a worse prognosis of KIRC patients. MTT assays and flow cytometry revealed that miltirone treatment induced KIRC cell pyroptosis and inhibited cell proliferation, with changes in the expression level of NLPR3, AIM2, caspase-3, and GSDMD. The enhancement of cell pyroptosis and the release of IL-1β and IL-18 cytokines were reversed by pretreatment with the pyroptosis inhibitor VX-765. CONCLUSIONS: Our study revealed the prognostic value of NLRP3 and AIM2 in KIRC. Miltirone treatment inhibited KIRC cell proliferation and enhanced cell pyroptosis via the NLRP3/AIM2/GSDMD axis. This study provides a novel molecular mechanism and potential therapeutic targets in KIRC progression.