ADAM and ADAMTS proteases as integrative hubs in heart failure pathogenesis and therapy.

Heart failure (HF) arises from multifactorial disruptions in cellular signaling, inflammation, and tissue remodeling beyond classical neurohormonal regulation. Increasing evidence highlights ADAM and ADAMTS metalloproteinases as central integrators of inflammatory, fibrotic, and hypertrophic pathways. This review establishes a dual integrative framework. Horizontally, distinct protease family members converge within each pathological axis, including inflammation, fibrosis, hypertrophy and remodeling, metabolism, and angiogenesis, to drive disease progression. Vertically, individual proteases, such as ADAM17, coordinate multiple axes through various effectors that activate distinct downstream pathways, exhibiting both detrimental and protective functions. These mechanistic insights guide the development of selective inhibitors to circumvent pitfalls associated with broad-spectrum MMP targeting. Additionally, emerging ADAM and ADAMTS family members show promise as diagnostic and prognostic biomarkers in cardiovascular diseases (CVDs). By synthesizing mechanistic depth with translational relevance, this framework reveals protease-centered opportunities for precision intervention and outlines essential future research directions.