Caffeic acid promoted deep vein thrombosis resolution in mice by suppressed macrophage M1 polarization through Keap1/Nrf2 pathway

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Abstract Background Deep vein thrombosis (DVT) carries significant health risks, with macrophages playing a key role in thrombus resolution. Caffeic acid (CA) has been shown to inhibit thrombosis, but its role in DVT resolution remains unclear. Purpose This study aimed to investigates the effects and mechanisms of CA in accelerating DVT resolution. Methods A stasis-type DVT model was established in mice via inferior vena cava ligation. The effects of CA were analyzed. Thrombus resolution was assessed using histological staining, gelatin zymography, immunoblotting, and immunofluorescence. Macrophage depletion was conducted with chlorophosphate liposomes, and bone marrow-derived macrophages (BMDMs) were used for polarization studies. RNA sequencing identified potential molecular pathways. Nrf2 gene-deficient mice were used to verify the role of Nrf2 in deep vein thrombus resolution. Results Caffeic acid reduced thrombus size, enhanced collagenolysis via increased MMP-2 activity, promoted neovascularization, increased macrophage infiltration, and suppressed M1 polarization and inflammation. CA activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by inhibiting Keap1, leading to enhanced antioxidant responses in both BMDMs and thrombus tissue. Macrophage depletion negated CA’s benefits, confirming the central role macrophages. Conclusion CA promoted early thrombus resolution via macrophage recruitment, M1 polarization suppression, and Nrf2 activation, highlighting its potential as a preventive strategy for DVT.

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