Targeting the NLRP3 inflammasome signalling in acute myeloid leukemia: Mechanisms, therapeutics, and future directions.

Acute myeloid leukemia (AML) is one of the most frequent hematological malignancies. It is a complex and aggressive disease of undifferentiated hematopoietic progenitor cells, with high rates of relapse and drug resistance, posing significant clinical challenges. Emerging evidence underscores the critical role of inflammation in AML progression, with inflammasomes-key regulators of the inflammatory response-emerging as pivotal players in disease pathogenesis. Among these, the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome has gained particular attention due to its involvement in promoting leukemogenesis and chemoresistance. While inflammasomes have been previously studied in various cancer types, no comprehensive review to date has specifically addressed the role of the NLRP3 inflammasome in AML and its potential targeted therapy. Focusing on the NLRP3 inflammasome, we explore its contribution to AML pathogenesis and its therapeutic potential. We highlight preclinical natural and synthetic compounds, alongside clinical-stage and clinically approved drugs that target the NLRP3 inflammasome signalling pathway and components. We address the challenges and limitations of these promising compounds and drugs, while highlighting recent advancements such as the synthesis of novel and derivatives designed to improve their efficacy. Finally, we discuss future research directions aimed at deepening our understanding of the NLRP3 inflammasome and identifying novel and improved therapeutic outcomes against AML.