Mechanism and Individualized Management of Hypertension Associated With Bruton Tyrosine Kinase Inhibitors: The PCSK9/Notch3 Signaling Pathway.

Abstract

Bruton's tyrosine kinase inhibitors (BTKIs) have become the first-line treatment for B-cell malignancies such as chronic lymphocytic leukemia, significantly improving patient outcomes. However, hypertension is a common and critical cardiovascular adverse effect of BTKIs, with incidence rates ranging from 23% to 75%. For some patients, traditional antihypertensive therapy is ineffective, creating significant risks to cardiovascular safety and the sustainability of the treatment plan. Current reviews have primarily addressed general BTKI cardiotoxicity or isolated signaling pathways, failing to systematically analyze how the proprotein convertase subtilisin/kexin type 9 (PCSK9)/Notch3 pathway coordinates hypertension. Furthermore, current reviews lack comprehensive integration of individual susceptibility and mechanism-targeted strategies. Thus, this review systematically evaluates the epidemiological characteristics, molecular mechanisms, individual risk-modifying factors, and management strategies of BTKI-related hypertension by searching the PubMed, Embase, and Web of Science databases (up to 2025). Key findings suggest that BTKIs induce endothelial dysfunction and increase peripheral mechanisms through multiple mechanisms. These agents promote vascular inflammation, remodeling, and altered lipid metabolism by upregulating PCSK9, abnormally activating Notch3 signaling, increasing renin-angiotensin-aldosterone system activity, and driving nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-reactive oxygen species-mediated oxidative stress. Additionally, off-target inhibition of TEC/interleukin 2-inducible T-cell kinase contributes to these adverse vascular effects. Disease risk is further modified by Notch3/PCSK9 gene polymorphisms and clinical features such as existing cardiovascular disease and advanced age. Clinical management primarily relies on traditional antihypertensive drugs such as angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, as well as calcium channel blockers. In contrast, novel intervention strategies such as PCSK9 inhibitors and curcumin show potential advantages. To our knowledge, this review systematically elaborates the core role of the PCSK9/Notch3 signaling pathway in BTKI-related hypertension, integrating the "mechanism - susceptibility - intervention" three-dimensional network, providing a theoretical basis for precise risk stratification and individualized treatment, and promoting the dual optimization of cardiovascular protection and anti-tumor therapy.