Biology subjects

Cai, Z.-Y.

Publications and source records attributed to Cai, Z.-Y..

4 recordsLinked to original sources

bioRxiv2026

Z-RNA-ZBP1 axis drives Tau-mediated neurodegeneration

Although the causes of Tau aggregates vary, once Tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimers disease (AD) being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting neurotoxicity of Tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in Tau-related neurodegeneration. Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements (TEs) that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from Heterochromatin Protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in AD patients was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged Tau-transgenic mice (24-month-old), highlighting the therapeutic potential of ZBP1 inhibition to strive against neurodegeneration in tauopathies.

neuroscience↗

bioRxiv2026

Oxidation-Driven mtDNA B-Z Transition Activates ZBP1 to Mediate Acetaminophen Hepatotoxicity

Acetaminophen (APAP) overdose induces mitochondrial damage in hepatocytes, leading to secondary toxicity that resists to N-acetylcysteine (NAC) treatment and culminates in hepatocyte death and acute liver failure (ALF)1. The underlying mechanisms remain poorly understood, often necessitating liver transplantation2. Here, we identify oxidative modification-driven B-to-Z transitions in mtDNA as the central pathological driver of APAP-induced ALF. Upon APAP exposure, oxidized mtDNA fragments leak into the cytosol, activating ZBP1 signaling via its Z domain. Genetic inhibition of ZBP1 mitigates liver damage and improves survival. Using synthetic 12-bp dGdC duplexes, we demonstrate that 8-oxoG substitution, even under physiological salt concentrations, is sufficient to induce Z-DNA formation, enabling specific ZBP1 binding through its Z domain. The 8-oxoG repair enzyme OGG13, activated by TH107854, removes 8-oxoG modifications and reverses Z-DNA to B-DNA conformation. In mice with lethal APAP toxicity, delayed NAC treatment results in 50% mortality. In contrast, TH10785 monotherapy increases survival to 90%, while its combination with NAC achieves 100% survival. These results define the oxidized mt Z-DNA-ZBP1 axis as a critical driver of APAP hepatotoxicity, providing fundamental insights into DNA conformational dynamics and therapeutic opportunities in drug-induced liver failure.

cell biology↗

bioRxiv2024

A ZBP1 isoform blocks ZBP1-mediated cell death

ZBP1 is an interferon-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA), a type of left-handed nucleic acid. More than that, the binding of ZBP1 with Z-NA promotes cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppresser of the inflammatory signaling mediated by full-length ZBP1. Compared with ZBP1, ZBP1-S protein has Z domains but no RHIM domains. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Z domains of ZBP1. Cells from mice (Rip1D325A/D325A) with Cleavage-resistant RIP1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-depedent cell death. Intriguingly, Rip1D325A/D325A cells go death spontaneously when ZBP1-S was deleted, indicating the cell death driven by ZPB1 is under the check of ZBP1-S. Thus, our findings reveal that alternative splicing of Zbp1 represents an autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against auto-inflammations. HighlightO_LIZBP1-short isoform is expressed synchronously with ZBP1. C_LIO_LIZBP1-short isoform counteracts ZBP1 mediated cell death. C_LIO_LIZBP1-S suppresses ZBP1 signaling in an Z-domain dependent manner. C_LIO_LIZBP1-S prevents the autoactivation of ZBP1 in Rip1D325A/D325A cells. C_LI

immunology↗

bioRxiv2021

Characterization of epigenetic alterations in esophageal cancer by whole-genome bisulfite sequencing

Esophageal carcinoma is a common and aggressive malignancy, and its patients have dismal clinical outcomes. The epigenetic dysregulation in both major subtypes, esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), awaits further characterization. Here, we perform whole-genome bisulfite sequencing (WGBS) on a total of 43 esophageal cancer and normal samples, generating one of the largest WGBS datasets in this cancer to date. Focusing on hypomethylated regions in cancer, we show that they are associated with increased chromatin activity and enhancer RNA expression. Using this large collection of WGBS dataset, we reveal and validate novel clusters in both ESCC and EAC. We further identify specific molecular features in each cluster, with potential clinical implications. These data together advance our understanding of the epigenetic alterations in esophageal cancer and provide a rich resource for the research community of this disease.

cancer biology↗