Chinese Medical Journal review highlights ZBP1’s role in programmed cell death and therapeutic potential

Programmed cell death, or PCD, is an actively regulated biological process in which cells undergo self-destruction in a controlled manner. This process is essential for maintaining tissue homeostasis and innate immunity, and it also plays a critical role in the pathology and treatment of various human diseases. Different types of PCD, including apoptosis, necroptosis, pyroptosis, and ferroptosis, involve specific internal signaling pathways within cells.

Nucleic acids, the biomolecules that store and transmit genetic information, are detected by the intracellular sensor Z-DNA binding protein 1 (ZBP1). This protein contains distinct domains that perform unique functions: the Zα domain recognizes endogenous or exogenous nucleic acids, while the RHIM domain senses or binds specific signaling molecules, thereby regulating various types of PCD. ZBP1 is involved in multiple pathological states, including infections, inflammation, neurological diseases, and cancer, influencing the onset and progression of these conditions.

In light of these findings, a team of researchers led by Professor Xian Jiang and Dr. Gu He from West China Hospital of Sichuan University conducted a comprehensive review of ZBP1-mediated PCD. “We wanted to do a comprehensive review, thoroughly summarizing the cellular and molecular mechanisms of PCD involving ZBP1,” mentioned Prof. Jiang, discussing the motivation behind their study. The review was published in the journal Chinese Medical Journal on 25 August 2025. The review compiles current knowledge on molecules interacting with ZBP1, examines downstream signaling pathways, and provides an in-depth analysis of how these mechanisms contribute to disease development. It also explores potential diagnostic and therapeutic strategies, proposing future directions for targeted ZBP1 inhibitors.

The article elaborates how the Zα domain allows ZBP1 to efficiently recognize endogenous or exogenous nucleic acids, particularly when cells produce nucleic acid molecules in response to viral infections or other external stimuli. When cells undergo such stress responses, ZBP1 can rapidly sense the abnormal nucleic acids and activate corresponding cell death signaling pathways via the interactions of the RHIM domain, regulating various types of programmed cell death.

The article also describes the different types of PCD and how ZBP1 is involved in the different signaling pathways. While apoptosis is a normal cell death mechanism, that maintains tissue homeostasis, necroptosis is involved in cell death during infection or inflammations.  “During apoptosis, ZBP1 may trigger cellular self-destruction by activating certain key apoptotic signaling pathways, while in the context of inflammation or infection, ZBP1 might promote necroptosis, leading to cellular swelling and lysis,” explained Dr. He, another researcher involved in the study. Additionally, ZBP1 is involved in novel types of cell death such as pyroptosis and ferroptosis, impacting cellular survival, damage, and repair through its fine-tuned regulation.

The review discusses various molecules interacting with ZBP1, including downstream signaling pathways and other key factors involved in cell death. This analysis provides deeper insights into how ZBP1 regulates the fate of cellular death and opens new directions for developing targeted therapeutic strategies against ZBP1. In recent times, multiple drugs are developed to target the small molecules involved in signaling pathways. Targeting ZBP1 can be particularly helpful in treating diseases associated with abnormal mechanisms of cell death, such as cancer and autoimmune diseases.

In disease research, ZBP1 acts as a crucial immune sensor that can identify viral nucleic acids and induce the host's antiviral immune response during viral infections. Therefore, ZBP1 plays a vital role in the process of viral clearance. Moreover, ZBP1 has a widespread regulatory role in both infectious and non-infectious diseases. This review also provides a detailed summary of the current relevant disease models. This includes various inflammatory diseases, cancer, nervous system-related diseases and others.

With advancements in technology, the development of targeted drugs related to PCD, such as those aimed at ZBP1, has gradually become a new research focus. The emergence of new tools, such as artificial intelligence, has also provided assistance in the research and development process. Through more in-depth studies, scientists hope to develop new therapies that can regulate the function of ZBP1, thereby promoting disease treatment and improving patient prognosis. The review emphasizes that a deeper understanding of the mechanisms by which ZBP1 participates in programmed cell death will provide a new theoretical basis for treating related diseases and advance clinical research.

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Referance

DOI: https://doi.org/10.1097/cm9.0000000000003737 

About Sichuan University

Sichuan University, located in Chengdu, Sichuan, China, is a leading public university formed by the merger of three former national universities: Sichuan University, Chengdu University of Science and Technology, and West China University of Medical Sciences. As one of China’s earliest higher education institutions, it offers 119 undergraduate programs across 12 fields, including arts, science, engineering, medicine, economics, management, law, history, philosophy, agriculture, and education. SCU promotes international collaboration, sending nearly 2,000 students annually to study abroad.

Website: https://en.scu.edu.cn/

About Professor Xian Jiang from West China Hospital of Sichuan University

Professor Xian Jiang is a chief physician and doctoral supervisor, currently serving as the Director of the Dermatology Department at West China Hospital of Sichuan University and the Dermatology Research Center at the Sichuan University Frontier Center. She is associated with multiple organizations and committees, including an academic and technical leader in Sichuan Province, a standing committee member of the 16th Committee of the Dermatology Branch of the Chinese Medical Association and the leader of the Laser Group. Her main research focus is on disfiguring skin diseases. She has authored more than 200 research papers till date.

About Dr. Gu He from West China Hospital of Sichuan University

Dr. Gu He is a researcher in the Dermatology Department of West China Hospital, Sichuan University, and at the National Key Laboratory for Biological Therapy. A doctoral supervisor and a young talent supported by the National High-Level Talent Special Support Program, his research focuses on identifying new therapeutic targets for chronic non-communicable diseases and developing targeted treatment drugs.

Funding information

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82273559, 82103757, and 82073473), the Department of Science and Technology of Sichuan Province (No. 2022YFQ0054), and Sichuan Natural Science Foundation Project (No. 2023NSFSC1554).