ADAMTS4 mediates LPS-induced cardiac injury and myocardial fibrosis through proteolytic cleavage of TSP1.
ZW, Z., SY, W., W, L., X, L., R, C., X, X., W, L., SY, S., MM, M., & QT, M. (2026). ADAMTS4 mediates LPS-induced cardiac injury and myocardial fibrosis through proteolytic cleavage of TSP1.. Clinical and translational medicine. https://doi.org/10.1002/ctm2.70769
ZW Z, SY W, W L, X L, R C, X X, et al. ADAMTS4 mediates LPS-induced cardiac injury and myocardial fibrosis through proteolytic cleavage of TSP1.. Clinical and translational medicine. 2026; doi: 10.1002/ctm2.70769
ZW Z, SY W, W L, et al. ADAMTS4 mediates LPS-induced cardiac injury and myocardial fibrosis through proteolytic cleavage of TSP1.[J]. Clinical and translational medicine. 2026. DOI: 10.1002/ctm2.70769.
@article{zw2026,
author = {Zhang ZW and Wan SY and Li W and Lu X and Chen R and Xing X and Lai W and Sheng SY and Mosebetsi MM and Meng QT},
title = {ADAMTS4 mediates LPS-induced cardiac injury and myocardial fibrosis through proteolytic cleavage of TSP1.},
journal = {Clinical and translational medicine},
year = {2026},
doi = {10.1002/ctm2.70769},
note = {PMID: 42557768},
}
TY - JOUR AU - Zhang ZW AU - Wan SY AU - Li W AU - Lu X AU - Chen R AU - Xing X AU - Lai W AU - Sheng SY AU - Mosebetsi MM AU - Meng QT TI - ADAMTS4 mediates LPS-induced cardiac injury and myocardial fibrosis through proteolytic cleavage of TSP1. T2 - Clinical and translational medicine PY - 2026 DO - 10.1002/ctm2.70769 AN - PMID:42557768 ER -
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.