NLRP3 inflammasome as a therapeutic target in doxorubicin-induced cardiotoxicity: role of phytochemicals

Abstract

Doxorubicin (DOX) has received widespread attention as a broad-spectrum antitumor drug. However, it has been a recognized challenge that long-term DOX injections can lead to severe cardiotoxicity. There are numerous interventions to DOX-induced cardiotoxicity, and the most cost-effective is phytochemicals. It has been reported that phytochemicals have complex and diverse biological properties, facilitating the mitigation of DOX-induced cardiotoxicity. DOX-induced cardiotoxicity has numerous pathological mechanisms, and the nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated cardiomyocyte pyroptosis is one of them. This review initially presents an overview of the pathological mechanisms that underlie cardiotoxicity induced by DOX. Subsequently, we present a comprehensive elucidation of the structure and activation of the NLRP3 inflammasome. Finally, we provide a detailed summary of phytochemicals that can mitigate DOX-induced cardiotoxicity by influencing the expression of the NLRP3 inflammasome in cardiomyocytes.

Keywords: DOX-induced cardiotoxicity; NLRP3 inflammasome; myocardial injury; phytochemicals; pyroptosis.

FIGURE 1

The main pathological mechanisms of doxorubicin-induced cardiotoxicity. Doxorubicin-induced cardiotoxicity involves multiple pathological mechanisms. The main can include oxidative stress, apoptosis, ferroptosis, pyroptosis, autophagy, inflammation, endoplasmic reticulum stress, epigenetics, Ca²⁺ overload, disturbed energy metabolism and mitochondrial dysfunction (Created with BioRender.com).

FIGURE 2

The activation process of NLRP3 inflammasome. The activation of NLRP3 inflammasome depends on two main signals. First is the “priming” signal. This signal is primarily mediated by a variety of PRRs, including TLRs. These receptors recognize PAMPs or DAMPs, thereby triggering the nuclear translocation of NF-κB. This process subsequently induces the transcription of NLRP3, IL-1β, and IL-18. The next is the “triggering” signal. The signal promotes NLRP3 oligomerization and NLRP3 interacts with ASC. ASC binds to pro-caspase-1 to form the NLRP3 inflammasome. Pro-caspase-1 is cleaved into active caspase-1, which activates pro-IL-1β, pro-IL-18 and GSDMD. Activated NT-GSDMD forms membrane pores, releasing IL-1β and IL-18 and inducing pyroptosis. This signal is triggered by factors like ion flow (K⁺ efflux, Na⁺ influx), ATP, pore-forming toxins, particulate matter and silica crystals (Created with BioRender.com). (PRRs, pattern recognition receptors; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; TLRs, toll-like receptors; NF-κB, nuclear factor kappa B; IκK, IkappaB kinase; IL-1β, interleukin-1beta; NLRP3, nod-like receptor family pyrin domain-containing 3; ASC, apoptosis-associated speckle-like protein; GSDMD, gasdermin-D; ATP, adenosine triphosphate; P2X7, purinergic 2X7).