{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:40:45Z","timestamp":1792190445256,"version":"4.4.0"},"reference-count":181,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Publish not Perish"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>In contrast to foreign nucleic acids, some of our own endogenously synthesized nucleic acids may become immunologically active without being considered \u201cforeign\u201d. For example, abnormalities in chromatin organization, transcription termination, ribonucleic acid (RNA) splicing, and RNA editing, together with damage to mitochondrial integrity, may render normally functional deoxyribonucleic acid (DNA) and RNA persistently available and aberrantly structured ligands for innate immunity. Z-DNA-binding protein 1 (ZBP1), recently identified as an important component of this innate immune system, recognizes both left-handed DNA (Z-DNA) and left-handed RNA (Z-RNA) using its tandem Z-alpha (Z\u03b1) domains and couples recognition of these conformational states to receptor-interacting serine\/threonine-protein kinase 1 (RIPK1)-, receptor-interacting serine\/threonine-protein kinase 3 (RIPK3)-, and mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent inflammatory and cell-death pathways. More recent studies have also shown that ZBP1 plays a role in recognizing damaged self-nucleic acids associated with tauopathies, Alzheimer\u2019s disease (AD), traumatic brain injury (TBI), and amyloid-associated neuroinflammation. The nucleic-acid forms associated with these conditions include transposable-element activation, extended repeat-containing transcripts, RNA\u2013RNA duplexes or RNA:DNA hybrids, oxidized mitochondrial DNA (mtDNA), and intercellularly transferred nucleic acids, all of which may exhibit substrate structures compatible with Z-form formation. Signaling by ZBP1 does not occur simply based upon nucleic-acid abundance; rather, signaling occurs after prolonged exposure to a nucleic acid when it persists in a structurally competent state, sufficient receptors are present to bind its exposed regions, the receptor proteoforms are competent to participate in signaling, receptor-interacting protein homotypic interaction motif (RHIM)-dependent assembly occurs, and the appropriate adaptor molecules are present. Furthermore, the identity of the cell type expressing ZBP1 determines whether the response produces RIPK3\u2013MLKL-dependent neuronal injury, microglia-mediated inflammation, apoptosis, or mixed cell death. Finally, competition with adenosine deaminase acting on RNA 1 (ADAR1), melanoma differentiation-associated protein 5 (MDA5), double-stranded RNA-dependent protein kinase (PKR), the cyclic guanosine monophosphate\u2013adenosine monophosphate synthase\u2013stimulator of interferon genes (cGAS\u2013STING) pathway, and other nucleic-acid-sensing proteins divides the available pool of endogenous nucleic acids among the outcomes of immune tolerance, type I interferon (IFN-I) signaling, translational inhibition, neuroinflammation, and necroptosis.<\/jats:p>","DOI":"10.3390\/ijms27167478","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:31:59Z","timestamp":1787304719000},"page":"7478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["ZBP1 in Neuroinflammation and Neurodegeneration: Z-Nucleic-Acid Sensing, RHIM Signalling and Therapeutic Targeting"],"prefix":"10.3390","volume":"27","author":[{"given":"Matei","family":"\u0218erban","sequence":"first","affiliation":[{"name":"Faculty of General Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Neurosurgery, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"},{"name":"Puls Med Association, 051885 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corneliu","family":"Toader","sequence":"additional","affiliation":[{"name":"Faculty of General Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Neurosurgery, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"},{"name":"Puls Med Association, 051885 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u0103zvan-Adrian","family":"Covache-Busuioc","sequence":"additional","affiliation":[{"name":"Faculty of General Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Neurosurgery, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"},{"name":"Puls Med Association, 051885 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7175","DOI":"10.1016\/j.cell.2025.10.013","article-title":"Mapping Chromatin Structure at Base-Pair Resolution Unveils a Unified Model of Cis-Regulatory Element Interactions","volume":"188","author":"Li","year":"2025","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1016\/j.bpj.2018.09.022","article-title":"DNA Local-Flexibility-Dependent Assembly of Phase-Separated Liquid Droplets","volume":"115","author":"Shakya","year":"2018","journal-title":"Biophys. 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