ADAMTS4 mediates LPS-induced cardiac injury and myocardial fibrosis through proteolytic cleavage of TSP1.

Septic cardiomyopathy is characterized by acute cardiac dysfunction, while sustained inflammatory and extracellular matrix remodeling may contribute to subsequent myocardial fibrosis and impaired cardiac recovery. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) has been linked to fibrotic remodelling, but its role in septic cardiac injury remains unclear. Here, we show that Adamts4 is upregulated in LPS-induced septic mouse hearts and is predominantly induced in cardiac fibroblasts. Using three fibroblast-lineage Adamts4 knockout models, we demonstrate that Adamts4 deletion attenuates LPS-induced cardiac dysfunction, inflammation and fibrosis, whereas Tcf21-lineage fibroblast Adamts4 overexpression aggravates these changes. Mechanistically, ADAMTS4 interacts with thrombospondin-1 (TSP1) and promotes its catalytic activity-dependent proteolytic processing. The 236-246 amino acid region of TSP1 is required for fragment generation and fibroblast activation. TSP1 processing further activates TGF-β/Smad and NF-κB signalling, promoting myofibroblast activation and extracellular matrix deposition. These findings identify ADAMTS4 as a fibroblast-centred driver of septic cardiac fibrosis and suggest that targeting the ADAMTS4-TSP1 axis may offer therapeutic potential for septic cardiomyopathy. KEY POINTS: ADAMTS4 is induced predominantly in cardiac fibroblasts after LPS challenge Fibroblast-lineage Adamts4 deletion attenuates LPS-induced cardiac dysfunction and fibrosis The TSP1 236-246 aa region is required for efficient ADAMTS4-dependent processing ADAMTS4-dependent TSP1 processing activates TGF-β/Smad and NF-κB signalling in fibroblasts.