Mitochondrial DNA mediated Kupffer cell activation in the pathogenesis and progression of liver diseases.

The liver serves as a pivotal metabolic and immunological hub, yet its homeostatic equilibrium is highly susceptible to mitochondrial dysfunction. Recent studies have implicated mitochondrial DNA (mtDNA) as an important damage-associated molecular pattern (DAMP) that links mitochondrial injury to sterile hepatic inflammation and KCs (KCs) activation. This review provides a comprehensive synthesis of the mtDNA mediated KCs across four major hepatic pathologies: Alcohol-associated Liver Disease (ALD), Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), Hepatic Ischemia-Reperfusion Injury (IRI), and Hepatocellular Carcinoma (HCC). We discuss emerging evidence that Z-DNA-binding protein 1 (ZBP1) associated PANoptosis and nerve injury-induced protein 1 (NINJ1) mediated plasma membrane rupture may contribute to inflammatory cell death in severe liver injury, complementing rather than superseding canonical pyroptotic mechanisms. However, the extent to which mtDNA directly activates this axis remains unresolved. Furthermore, we delineate the cell-type-specific dichotomy of cyclic GMP-AMP synthase (cGAS) signaling, which fuels pro-inflammatory storms in KCs via the stimulator of interferon genes (STING) pathway while promoting protective mitophagy in hepatocytes through a STING-independent cGAS-Beclin-1 interaction. In the context of immunometabolism, we also summarize preclinical evidence linking cytidine/uridine monophosphate kinase 2 (CMPK2) dependent mtDNA synthesis to inflammasome activation and mitochondrial calcium uniporter (MCU) acetylation to age-associated mtDNA release during IRI. Finally, we evaluate the clinical translational potential of targeting these molecular hubs and the emergence of cell-free mitochondrial DNA (cf-mtDNA) fragmentomics-including 5' end motif analysis and diversity scoring as a transformative liquid biopsy tool for precision diagnosis. Collectively, available evidence positions mtDNA mediated KCs activation as an important, context-dependent contributor to liver disease and a potential therapeutic target, while underscoring the need for cell-specific and human validation.