NLRP3/IL-1 and MyD-88/CCL2 pathway were reduced by inclisiran under exposure to anthracyclines and HER-2 blocking agent

Abstract Background Anthracyclines and trastuzumab-related cardiotoxicity represents a significant clinical challenge in cancer therapy, often limiting treatment efficacy and patient survival. The underlying mechanisms of cardiotoxicity involve the activation of NLRP3 and the MyD88-dependent signaling pathway. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), such as inclisiran, are known for their lipid-lowering effects, but emerging data indicates that they may also exert pleiotropic benefits beyond cholesterol reduction. This study investigates whether inclisiran can mitigate the cardiotoxic effects of anthracyclines and trastuzumab through reduction of NLRP3 activation and MyD88 signaling, independently of its effects on dyslipidemia. Purpose To evaluate whether inclisiran reduces anthracycline and trastuzumab-induced cardiotoxicity by modulating NLRP3 and MyD88 signaling, independent of its effects on dyslipidemia. Methods Human cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin, (200 nM) and trastuzumab in sequential therapy (200 nM), alone or in combination with inclisiran (100 nM) for 72h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3; expression of MyD88/CCL2; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and expression of cytokines involved in cardiotoxicity (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IFN-γ, TNF-α, G-CSF, GM-CSF). Results Inclisiran co-incubated with doxorubicin and trastuzumab exerts significant cardioprotective effects enhancing cell viability of 88,9 % compared to only DOXO/TRA treated cells (p0,001 for all). Cell necrosis and apoptosis were reduced. Significant reduction of oxidative stress, ferroptosis and intracellular levels of NLRP-3, MyD88, CCL-2, p65NF-KB, IL-1α, IL-1β, IL-6, IL-12, IL17-α, TNF-α, G-CSF were seen in inclisuran group vs only DOXO/TRA group (p0.001). Conclusion For the first time, PCSK9i inclisuran exerts significant anti-inflammatory effects to reduce anthracycline-HER-2 blokcing agent mediated cardiotoxicity through NLRP-3 and Myd-88 related pathways. The overall picture of the study warrent on the use of PCSK9i in primary prevention of CTRCD in cancer patients, independently from dyslipidemia.