Background and Aims Heart failure (HF) is a leading cause of mortality worldwide and characterized by significant co-morbidities and dismal prognosis. Neutrophil extracellular traps (NETs) aggravate inflammation in various cardiovascular diseases; however, their function and mechanism of action in HF pathogenesis remain underexplored. This study aimed to investigate the involvement of a novel VWF-SLC44A2-NET axis in HF progression.Methods NET levels were examined in patients with HF and mouse models of transverse aortic constriction (TAC) HF. PAD4 knockout mice and NET inhibitors (GSK-484, DNase I, NEi) were used to evaluate the role of NETs in HF. RNA sequencing was used to investigate the downstream mechanisms. Recombinant human ADAMTS13 (rhADAMTS13), ADAMTS13, and SLC44A2 knockouts were used to identify novel upstream factors of NETs.Results Elevated NET levels were observed in patients with HF and TAC mouse models of HF. PAD4 knockout and NET inhibitors improved the cardiac function. Mechanistically, NETs induced mitochondrial dysfunction in cardiomyocytes, inhibiting mitochondrial biogenesis via the NE-TLR4-mediated suppression of PGC-1 alpha. Furthermore, VWF/ADAMTS13 regulated NET formation via SLC44A2. Additionally, sacubitril/valsartan amplifies the cardioprotective effects of the VWF-SLC44A2-NET axis blockade.Conclusions This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment. Structured Graphical Abstract Elevated levels of NETs were detected in patients and mouse models of HF, contributing to the pathogenesis of the disease. Mechanistically, VWF triggered the generation of NETs through the involvement of SLC44A2 on neutrophils. NETs hindered mitochondrial biogenesis by suppressing PGC-1 alpha through the NE-TLR4 pathway. Targeting the VWF-SLC44A2-NET axis led to improvements in the cardiac histology and function. HF, heart failure; LV, left ventricular; MI, myocardial ischaemia; NE, neutrophil elastase; NET, neutrophil extracellular trap; PGC-1 alpha, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SLC44A2, solute carrier family 44 member 2; TAC, transverse aortic constriction; TCA, tricyclic acid; TLR4, Toll-like receptor-4; VWF, von Willebrand factor