Voriconazole-induced hepatic steatosis driven by TREM1-TLR4 activation; LR12 peptide inhibits inflammation and lipid accumulation.

Voriconazole (VCZ), a widely used antifungal, frequently causes hepatotoxicity, including hepatic steatosis, which currently lacks effective early biomarkers and targeted interventions. This presents a significant clinical challenge, as liver injury can progress silently. The triggering receptor expressed on myeloid cells-1 (TREM1) is known to amplify inflammatory responses, particularly in myeloid cells like macrophages, which are crucial in liver pathology. Understanding how TREM1 integrates inflammation and metabolic dysregulation in VCZ-induced liver injury could reveal novel diagnostic and therapeutic avenues, addressing a critical gap in managing antifungal-related adverse effects.

Researchers investigated TREM1's role in voriconazole-induced hepatic steatosis using a multi-pronged approach. Clinical correlations were assessed by measuring plasma soluble TREM1 (sTREM1) levels in patients receiving voriconazole, linking them to liver injury severity. Mechanistic studies involved macrophage-specific depletion, Trem1 knockout and overexpression models in mice, and macrophage-hepatocyte co-cultures. Molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation (Co-IP) validated VCZ-TREM1 binding. Pathway inhibition assays utilized the LR12 peptide to target TREM1 signaling in murine models, with outcomes assessed via integrated multi-omics profiling.

In patients, elevated plasma sTREM1 levels correlated significantly with the severity of voriconazole-induced liver injury, indicating its potential as an early diagnostic marker. Mechanistically, voriconazole directly bound to TREM1, promoting the formation of TREM1-Toll-like receptor 4 (TLR4) complexes. This interaction activated a 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 subsequent 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 using the LR12 peptide effectively suppressed TREM1 signaling and attenuated both inflammatory and metabolic alterations in murine models. This study elucidated a novel TREM1-centered network linking VCZ-induced inflammation to steatosis.

LR12 peptide treatment significantly suppressed TREM1 signaling, leading to attenuated inflammatory and metabolic alterations in murine models of voriconazole-induced hepatic steatosis.