Open Access

REVIEW

Involvement of ZBP1 in Cancer and Its Potential Therapeutic Target Effects

Emmanuel Mago¹, Jiayi Xu¹, Dan Weng^1,*, Yan Pan^2,*

1 School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210000, China
2 School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

* Corresponding Authors: Dan Weng. Email: ; Yan Pan. Email:

(This article belongs to the Special Issue: Cell Death and Inflammation in Signaling and Diseases)

BIOCELL 2025, 49(3), 381-398. https://doi.org/10.32604/biocell.2025.059432

Received 08 October 2024; Accepted 25 December 2024; Issue published 01 April 2025

Abstract

Z-DNA binding protein 1 (ZBP1) has emerged as a critical player in cancer biology, functioning as a cytosolic nucleic acid sensor that triggers PANoptosis, a form of programmed cell death that integrates pyroptosis, apoptosis, and necroptosis. Although ZBP1 was initially recognized for its role in antiviral defense, recent research has highlighted its importance in the tumor microenvironment (TME), where it is essential for suppressing tumor growth and proliferation. This review explores the multifaceted role of ZBP1 in various cancer types, emphasizing its ability to detect Z-nucleic acids and double-stranded RNAs, leading to the initiation of PANoptosis through receptor-interacting protein homotypic interaction motif (RHIM)-dependent interactions. However, the antitumor potential of ZBP1 involves adenosine deaminase RNA specific 1 (ADAR1), particularly its ADAR1-P150 isoform (150 kDa), which inhibits ZBP1-mediated cell death, thereby promoting tumor progression. This has spurred interest in the development of ADAR1 inhibitors and combination therapies with US Food and Drug Administration (FDA)-approved agents such as interferon-α (IFN-α) to increase ZBP1 activity. Promising studies have demonstrated that ZBP1 regulation can significantly impact tumor suppression, particularly in necrotic tumors, where its expression is correlated with reduced tumor growth. Furthermore, oligomerization of telomeric repeat-containing RNA (TERRA)-bound ZBP1 on the mitochondrial membrane has been linked to mitochondrial antiviral signaling (MAVS)-induced interferon responses, adding another layer to the tumor-suppressive functions of ZBP1. Clinical investigations into nuclear export inhibitors (NEIs) such as KPT-330 and KPT-8602, in combination with IFN therapy, have shown potential in harnessing ZBP1 to induce PANoptosis and suppress tumor growth. Additionally, the small molecule curaxin CBL0137 has been identified as a promising agent for reversing immune checkpoint blockade (ICB) resistance by inducing Z-DNA (Z form DNA) formation and ZBP1-mediated necroptosis in tumor fibroblasts. This review consolidates recent advancements in ZBP1 research, highlighting its therapeutic potential as a target for cancer treatment and its promising role in overcoming resistance to existing therapies.

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Keywords

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