NLRP3 inflammasome inhibition emerges as a key strategy to mitigate chemotherapy-induced cardiotoxicity

Chemotherapy-induced cardiotoxicity represents a significant challenge in cancer treatment, leading to long-term morbidity and reduced quality of life for survivors. Current standard-of-care often falls short in fully preventing this damage. While factors like oxidative stress and mitochondrial dysfunction are known, the NLRP3 inflammasome has been identified as a crucial molecular link between chemotherapeutic stress and inflammatory cardiomyocyte death, driving myocardial inflammation and structural damage.

This comprehensive review integrates current knowledge on the NLRP3 inflammasome's structure, priming, activation pathways, and downstream signaling in the context of chemotherapy-induced cardiotoxicity. It goes beyond traditional doxorubicin-centered treatments to illustrate the broader impact of inflammasome-mediated pathophysiology. The authors also provide an overview of the therapeutic landscape, detailing both selective synthetic NLRP3 inhibitors and natural modulators.

The review highlights that NLRP3 activation is a central process in chemotherapy-induced cardiotoxicity, stimulating Gasdermin D-dependent pyroptosis and caspase-1-mediated upregulation of IL-1β and IL-18. Mitochondrial ROS-induced dissociation of TXNIP is identified as a key upstream event promoting NLRP3 activation across various chemotherapeutic classes. > The therapeutic landscape includes synthetic inhibitors like MCC950, CY-09, OLT1177 (dapansutrile), and tranilast, which exhibit strong target specificity by suppressing NACHT ATPase activity, preventing ASC oligomerization, or inhibiting NEK7-dependent assembly. Natural compounds such as oridonin, curcumin, resveratrol, honokiol, and flavonoids offer broader antioxidant and anti-inflammatory actions with favorable safety profiles. Emerging evidence suggests synergistic benefits when NLRP3 inhibition is combined with antioxidants or established cardioprotective agents.