Z-DNA binding protein 1 (ZBP1): Molecular mechanisms and therapeutic significance in metabolic diseases.

Abstract

Metabolic diseases are characterized by persistent disturbances in glucose, lipid, and energy homeostasis and include obesity, type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and related cardiovascular complications. Chronic inflammation, mitochondrial dysfunction, and dysregulated cell death contribute substantially to their progression. Identifying molecular sensors that connect metabolic stress with inflammatory tissue injury may therefore reveal new targets for disease intervention. Z-DNA-binding protein 1 (ZBP1) is a conformation-selective nucleic acid sensor that couples Z-DNA/Z-RNA recognition to RIPK-dependent inflammatory signaling and regulated cell death. Emerging preclinical evidence implicates dysregulated ZBP1 signaling in atherosclerosis, metabolic liver injury, diabetes-associated renal damage, and metabolic stress-related cardiac and neurological complications. This review examines the structural basis and regulatory mechanisms of ZBP1 activation and discusses its potential involvement in sterile inflammation, mitochondrial stress, immunometabolic remodeling, and PANoptosis. Emerging approaches for modulating ZBP1 signaling are also evaluated according to their degree of direct target engagement and translational maturity. Current evidence supports ZBP1 as a context-dependent link between abnormal nucleic acid sensing and metabolic tissue injury, although its disease specificity, therapeutic window, and clinical relevance remain uncertain.