Targeting NLRP3 inflammasome to mitigate chemotherapy-induced cardiotoxicity: advances in selective inhibitors and natural modulators.

Chemotherapy-induced cardiotoxicity is a significant difficulty in chemotherapy, contributing to long-term morbidity and reduced quality of life among cancer survivors. The NLRP3 inflammasome is a crucial molecular association between chemotherapeutic stress and inflammatory cardiomyocyte death, despite the fact that oxidative stress, mitochondrial dysfunction, calcium imbalance, and endothelial injury are well-known factors. NLRP3 activation increases myocardial inflammation and structural damage by stimulating Gasdermin D-dependent pyroptosis and caspase-1-mediated upregulation of IL-1β and IL-18. Another important upstream process that promotes NLRP3 activation during chemotherapy exposure is mitochondrial ROS-induced dissociation of TXNIP. Anthracyclines, antimetabolites, alkylating agents, platinum compounds, and microtubule inhibitors are just a few of the chemotherapeutic classes in which NLRP3 is involved. This review integrates current knowledge of NLRP3 structure, priming and activation pathways, and downstream signalling. This broader perspective illustrates the wider impact of inflammasome-mediated pathophysiology in chemotherapy-induced cardiac failure and goes beyond traditional doxorubicin-centered treatments. The review also provides an overview of the therapeutic landscape of selective NLRP3 inhibition, including natural modulators such as oridonin, curcumin, resveratrol, honokiol, and flavonoids, as well as synthetic inhibitors such as MCC950, CY-09, OLT1177 (dapansutrile), and tranilast. Synthetic molecules exhibit strong target specificity by suppressing NACHT ATPase activity, preventing ASC oligomerization, or inhibiting NEK7-dependent assembly, whereas natural compounds provide broader antioxidant and anti-inflammatory actions with favourable safety. Emerging evidence suggests synergistic benefits when NLRP3 inhibition is paired with antioxidants or established cardioprotective agents. Despite encouraging preclinical findings, translational challenges remain, including long-term safety assessment. Modulation of NLRP3 inflammasome activation has emerged as a potential intervention to limit chemotherapy-induced cardiac injury and dysfunction in cardio-oncology.