TREM1-mediated macrophage activation drives voriconazole-induced hepatic steatosis: Diagnostic and therapeutic implications

Voriconazole (VCZ)–induced hepatotoxicity lacks effective early biomarkers and targeted interventions. This study investigated the role of triggering receptor expressed on myeloid cells-1 (TREM1) as a central integrator of macrophage-driven inflammation and metabolic dysregulation in voriconazole-associated hepatic steatosis. Clinical correlations between plasma soluble TREM1 (sTREM1) and liver injury severity were assessed in patients treated with voriconazole. Mechanistic studies utilized macrophage-specific depletion, macrophage–specific Trem1 knockout and overexpression models, macrophage-hepatocyte co-cultures, and integrated multi-omics profiling. VCZ–TREM1 binding was validated through molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation (Co-IP), with pathway inhibition assays conducted using the LR12 peptide. In patients, elevated sTREM1’s levels correlated with the severity of liver injury, indicating its potential as an early diagnostic marker. Voriconazole directly bound to TREM1, promoting the formation of TREM1–Toll-like receptor 4 (TLR4) complexes, which activated phosphoinositide 3-kinase (PI3K)/Protein kinase B (AKT)–nuclear factor kappa-B (NF-κB)–NOD-like receptor thermal protein domain associated protein 3 (NLRP3)–interleukin-1beta (IL-1β) signaling cascade. The resulting overproduction of IL-1β induced hepatocyte lipid accumulation through reactive oxygen species (ROS)–mediated activation of sterol regulatory element-binding protein 1 (SREBP1)–driven lipogenesis. Pharmacological inhibition of TREM1 (LR12 peptide) suppressed TREM1 signaling and attenuated both inflammatory and metabolic alterations in murine models. This study elucidated a TREM1–centered signaling network linking voriconazole-induced inflammation to steatosis. sTREM1 showed potential as a translational biomarker for early detection of liver injury, and TREM1 inhibition (LR12) offers a promising therapeutic strategy for antifungal-related hepatotoxicity.