FGL2‐HDAC11 Drives Immunothrombosis via NETs‐Mediated Endothelial Capillarization in MASLD Fibrosis

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Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is frequently accompanied by hepatic fibrosis and systemic cardiovascular complications; however, the mechanistic interplay between coagulation abnormalities and disease progression remains poorly defined. Here, analyses of liver tissues and plasma from patients with MASLD, together with complementary mouse models, suggest an important role of immunothrombosis in fibrotic progression. In MASLD mouse models, pharmacological anticoagulation with dabigatran or aspirin attenuates fibrosis but increases systemic bleeding risk, highlighting the need for more selective strategies. Mechanistically, neutrophil extracellular traps (NETs) promote localized fibrin deposition within the hepatic microvasculature, leading to impaired microcirculation and liver sinusoidal endothelial cell (LSEC) capillarization associated with increased Piezo1‐dependent mechanosensation, thereby exacerbating fibrosis. Further investigation identifies neutrophil‐derived fibrinogen‐like protein 2 (FGL2) as a key upstream regulator of NETs formation through interaction with histone deacetylase 11 (HDAC11), promoting histone H3 deacetylation and facilitating PAD4‐mediated citrullination to drive NETs release. Genetic disruption of FGL2 or NETs inhibition restores LSEC fenestration, improves microvascular hemodynamics, and attenuates fibrosis without increasing systemic bleeding risk. Together, these findings define an immunothrombotic axis linking neutrophil‐derived FGL2–HDAC11 signaling to NETs formation and endothelial dysfunction in MASLD, providing mechanistic insight into the interplay between coagulation and metabolic liver disease.
Funding Information
  • National Key Research and Development Program of China (2023YFC2308600)
  • National Natural Science Foundation of China (82370609)
  • National Natural Science Foundation of China (82170596)

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