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

Jing Liu; Mingxia Deng; Xiaoying He; Jing Ma; Li Zhang; Xi Yang; Jinyao Dai; Shaohua Dong; Yichun Zhang; Zhijuan Zhang; Shuaibing Ying; Haoyang Hu; Lushun Jiang; Yujing Wang; Yunqing Qiu; Yan Lou

doi:10.1016/j.jpha.2025.101540

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Article Navigation > Journal of Pharmaceutical Analysis > 2026 > Accepted Manu

Jing Liu, Mingxia Deng, Xiaoying He, Jing Ma, Li Zhang, Xi Yang, Jinyao Dai, Shaohua Dong, Yichun Zhang, Zhijuan Zhang, Shuaibing Ying, Haoyang Hu, Lushun Jiang, Yujing Wang, Yunqing Qiu, Yan Lou. TREM1-mediated macrophage activation drives voriconazole-induced hepatic steatosis: Diagnostic and therapeutic implications[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101540

Citation:

Jing Liu, Mingxia Deng, Xiaoying He, Jing Ma, Li Zhang, Xi Yang, Jinyao Dai, Shaohua Dong, Yichun Zhang, Zhijuan Zhang, Shuaibing Ying, Haoyang Hu, Lushun Jiang, Yujing Wang, Yunqing Qiu, Yan Lou. TREM1-mediated macrophage activation drives voriconazole-induced hepatic steatosis: Diagnostic and therapeutic implications[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101540

Citation:

Jing Liu, Mingxia Deng, Xiaoying He, Jing Ma, Li Zhang, Xi Yang, Jinyao Dai, Shaohua Dong, Yichun Zhang, Zhijuan Zhang, Shuaibing Ying, Haoyang Hu, Lushun Jiang, Yujing Wang, Yunqing Qiu, Yan Lou. TREM1-mediated macrophage activation drives voriconazole-induced hepatic steatosis: Diagnostic and therapeutic implications[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101540

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

doi: 10.1016/j.jpha.2025.101540

1. Department of Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China;
2. Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, 311121, China;
3. Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China

Funds:

This work was supported by the Major Project under the Basic Public Welfare Research Program of Zhejiang Province (Grant No.: LD22H190003), Major Program of National Natural Science Foundation of China (Grant No.: 92369107), International Cooperation and Exchange Programs of the National Natural Science Foundation of China (Grant Nos.: W2412017 and 2024VTJP1003), Key Project under the Zhejiang Provincial and Ministry Co-construction Plan (Grant No.: WKJ-ZJ-2425), National Key Research and Development Program of China (Grant No.: 2023YFC2604300), and key Project of Zhejiang Medical Association of China (Grant No.: 2021ZYC-Z01). We thank Professor Chengfu Xu for his valuable comments on this article.

Received Date: Jul. 05, 2025
Accepted Date: Dec. 23, 2025
Rev Recd Date: Dec. 23, 2025
Available Online: Jan. 07, 2026

Abstract

Abstract

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.
- Macrophage,
- TREM1,
- Hepatic steatosis,
- Inflammation,
- Drug-induced liver injury

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References(50)

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