Zanubrutinib Ameliorates Cardiac Fibrosis and Inflammation Induced by Chronic Sympathetic Activation

Abstract

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which have now become a severe public health problem worldwide. β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous research has demonstrated that Bruton’s tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-β related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by β-AR overactivation; (2) Methods: In vivo: Male C57BL/6J mice were treated with or without the β-AR agonist isoproterenol (ISO) to establish a cardiac fibrosis animal model; (3) Results: In vivo: Results showed that the BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by β-AR. In vitro: Results showed that ZB alleviated β-AR-induced cardiac fibroblast activation and macrophage pro-inflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited β-AR-induced cardiac fibrosis and inflammation by the BTK, STAT3, NF-κB, and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates β-AR-induced cardiac fibrosis and inflammation.

Zanubrutinib ameliorates experimental idiopathic inflammatory myopathy-associated interstitial lung disease by BTK/NF-κB signaling pathway

“…We have compiled the previous research on anti-organ brosis drugs in our research group, as well as summarized the pharmacological and pathogenic mechanisms. Considering the alleviating effect of zanubrutinib on cardiac brosis [11] , its protective effect on acute lung injury [9] , and the alleviating effect of bortezomib-induced lung injury in mice [10] , we ultimately discovered that zanubrutinib can effectively alleviate the progression of experimental IIM-ILD. To the best of our knowledge, this is the rst evaluation of the dual inhibitory effect of a BTK inhibitor on both IIM and ILD in an IIM-related ILD animal model.…”

“…Zanubrutinib is a second-generation BTK inhibitor that exhibits stronger BTK target occupancy and lower off-target effects compared to the rst-generation BTK inhibitor, ibrutinib. Current research has found that Zanubrutinib has good e cacy in LPS-induced acute lung injury [9] , bleomycin-induced pulmonary brosis in mice [10] , and sympathetic stress-induced cardiac brosis [11] .…”