Ursodeoxycholic acid attenuates sepsis-associated platelet dysfunction through TREM2-linked signaling.

Sepsis remains a major clinical challenge characterized by immune dysregulation and coagulopathy. Ursodeoxycholic acid (UDCA) has been suggested to confer benefit in sepsis, but its mechanism remains unclear. This study explored whether UDCA modulates platelet function during sepsis via triggering receptor expressed on myeloid cells 2 (TREM2), an immunoreceptor with an emerging role in platelet biology. We employed an integrated strategy combining a retrospective cohort of 6476 sepsis patients (MIMIC-IV) with exploratory causal mediation analysis, mechanistic studies in LPS-induced septic and TREM2-knockout mice, computational docking suggesting a potential interaction between UDCA and TREM2, and a prospective pilot study in 8 septic patients receiving UDCA. Retrospective analysis showed that UDCA was associated with reduced hospital mortality (total effect -0.2287, P < 0.001), with 69.8% of this association mediated by increased platelet counts (natural indirect effect -0.1597, P < 0.001). Mechanistically, LPS downregulated platelet TREM2 and increased Syk-PI3K-Akt phosphorylation, accompanied by platelet hyperactivation. UDCA was associated with increased TREM2 expression and attenuated downstream signaling, and these effects were attenuated or not observed in TREM2-knockout mice. In the pilot clinical study, UDCA increased platelet counts (from 161.6 ± 106.2 to 211.4 ± 100.1 × 109/L, P = 0.001) and selectively inhibited ADP-induced aggregation (from 49.23 ± 20.45% to 31.63 ± 26.28%, P = 0.001) without significantly altering global coagulation parameters. In conclusion, these findings suggest that UDCA may be associated with improved sepsis outcomes by modulating platelet homeostasis in a TREM2-associated manner, providing preliminary translational support for TREM2 as a potential target in sepsis-associated coagulopathy.