Epigenetic regulation of NLRP3 by ACLY–PLAC8 axis sustains metabolic adaptation in triple-negative breast cancer

Abstract Cell metabolism is intricately interconnected with various pathological processes, including metabolic disorders, chronic inflammation, and tumor progression. Dysregulated lipid metabolism can result in mitochondrial dysfunction and excessive reactive oxygen species accumulation, which are well-established triggers for inflammasome activation. However, their functional relevance in triple-negative breast cancer (TNBC) remains largely unexplored. Here, we report that Adenosine triphosphate–citrate lyase (ACLY) expression is markedly upregulated in proliferating TNBC cells, where it promotes PLAC8 transcription through enhanced H3K27 histone acetylation. Consequently, the ACLY-PLAC8 regulatory axis profoundly influences both lipid and glucose metabolism in TNBC cells. Mechanistically, we identify that PLAC8 promotes NLRP3 transcription in an inflammasome-independent manner. Functionally, blockade of the ACLY/PLAC8 pathway significantly attenuates the oncogenic effects of TNBC cells in vitro and in vivo. Collectively, our study uncovers a novel mechanism by which ACLY induces PLAC8 expression to enhance NLRP3 transcription, thereby maintaining metabolic homeostasis in TNBC. These findings suggest that the ACLY/PLAC8 signaling axis may represent a potential therapeutic target for metabolic intervention in TNBC.