A collaborative team led by Dr. Zhong Fang and Professor Zhenghong Yuan at Fudan University Shanghai Medical College, together with Dr. Li Zhu at the Fifth People's Hospital of Suzhou (Suzhou University Affiliated Infectious Diseases Hospital), published a study in Volume 2, Article Number 30 of the journal Immunity & Inflammation on July 9, 2026. The study combines clinical drug-induced liver injury cohorts with acetaminophen (APAP)-induced liver injury mouse models to uncover a previously unknown self-protective mechanism in the liver.
The liver has long been considered an immune-privileged organ. When exposed to pathogens, such as the hepatitis B virus, its immune microenvironment tends to induce tolerance rather than immune activation—a property essential for maintaining systemic homeostasis and preventing excessive inflammatory damage. This unique characteristic is closely linked to the liver's structure and its resident immune cells and molecular signals, yet the specific mechanisms have remained incompletely understood.
The research team first discovered that in mouse models of APAP-induced liver injury, the liver expressed large amounts of Tim-3, and serum levels of soluble Tim-3 (sTim-3) increased significantly with higher APAP doses. To investigate whether Tim-3 played a protective role, the researchers administered Tim-3 blocking antibodies to mice and observed exacerbated liver injury, suggesting that Tim-3 indeed provides protection against liver damage.
Given the abundant levels of sTim-3 in the serum, the team treated APAP model mice with recombinant Tim-3 protein lacking the transmembrane domain. Remarkably, exogenous Tim-3 effectively reduced mortality, alleviated hepatic necrosis, and suppressed elevations in transaminases and inflammatory cytokines. Consistent protective effects were observed when exogenous Tim-3 was administered to Tim-3 global knockout mice, confirming that sTim-3—rather than membrane-bound Tim-3—is the functional form responsible for liver protection. Single-nucleus RNA sequencing analysis revealed that exogenous Tim-3 treatment significantly reduced the infiltration of immune cells, particularly monocyte-macrophages, into liver tissue.
Through immunohistochemistry and snRNA-seq analysis, the researchers identified hepatocytes, rather than immune cells, as the predominant source of Tim-3 expression. Importantly, hepatocytes also expressed ADAM molecules capable of cleaving the transmembrane region, making them the primary source of circulating sTim-3. Using a Cre-Flox system to generate hepatocyte-specific Havcr2 (Tim-3 gene) knockout mice, the team found that these animals not only had reduced serum Tim-3 protein after APAP challenge but also exhibited more severe liver injury with significantly elevated transaminase levels. The study further identified Galectin-3 and Galectin-9 as downstream ligands of sTim-3, and blocking the interaction between sTim-3 and these ligands also exacerbated liver injury.
Through clinical cohorts and public databases, the researchers confirmed that sTim-3 is present in the serum of patients with drug-induced liver injury, with levels increasing as liver injury worsens. Notably, when sTim-3 rose above 1.5 ng/mL, the correlation with transaminase levels reversed—consistent with the mouse model findings that APAP induces sTim-3 expression and that elevated sTim-3 provides protective feedback against liver injury. Multiplex immunohistochemistry of clinical liver biopsy specimens confirmed that hepatocytes co-express Tim-3 and ADAM molecules, whereas liver non-parenchymal cells express Tim-3 but lack ADAMs, explaining why only hepatocytes can release sTim-3.
In summary, this study reveals an autocrine feedback mechanism: drug-induced liver injury stimulates hepatocytes to express Tim-3, which is then cleaved by ADAMs and released into the extracellular space as sTim-3. sTim-3 binds to Galectin-3 and Galectin-9 to regulate immune cell infiltration into liver tissue, thereby protecting the liver from subsequent damage. “ This discovery not only advances understanding of the liver's self-protective mechanisms but also identifies sTim-3 as a promising therapeutic target for drug-induced liver injury, ” the authors concluded.
Reference
Title of original paper: Hepatocyte-derived soluble Tim-3 contributes to alleviating acetaminophen-induced liver injury
Journal: Immunity & Inflammation
DOI: https://doi.org/10.1007/s44466-026-00047-z
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Dr. Zhong Fang from Fudan University, China
Dr. Zhong Fang is an Assistant Research Fellow at Fudan University. He has received support from the National Natural Science Foundation Original Exploration Program, the Shanghai Natural Science Foundation, and the National Key Research and Development Program. His research focuses on liver immune tolerance mechanisms, chronic liver infection and carcinogenesis, and immunotherapy.
About Professor Zhenghong Yuan from Fudan University, China
Zhenghong Yuan is a Professor at Fudan University School of Basic Medical Sciences and a member of the Advisory Committee of the Chinese Academy of Medical Sciences. He has been honored with the National Science and Technology Progress Award (Special Class), the Ministry of Education Natural Science Award (First Class), and the Shanghai Natural Science Award (First Class), and has received the National Science Fund for Distinguished Young Scholars. His research focuses on liver HBV infection and immune system interactions.
About Dr. Li Zhu from Suzhou University, China
Dr. Li Zhu is a Chief Physician at the Fifth People's Hospital of Suzhou (Suzhou University Affiliated Infectious Diseases Hospital). She is a member of the Jiangsu "333" Engineering Training Program and a Key Talent of the Gusu Health Talent Program. Her research focuses on the prevention and treatment of liver diseases and their complications.
Funding information
This work was supported by the National Key R&D Program of China (2024YFC2311003), the National Natural Science Foundation of China (82550001), the Natural Science Foundation of Shanghai (25ZR1401050), the Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project of China (2026ZD01912300), and Suzhou Science and Technology Program (SYW2024036 and SYW2024034).
Immunity & Inflammation
Experimental study
Animals
Hepatocyte-derived soluble Tim-3 contributes to alleviating acetaminophen-induced liver injury
9-Jul-2026
The authors declare no competing interests.