Mitochondrial dysfunction in sepsis-induced liver injury: from pathophysiology to preclinical therapeutic targets.

Sepsis, defined as a life-threatening organ dysfunction arising from a dysregulated host response to infection, often culminates in multiple organ dysfunction syndrome (MODS). The liver, central to metabolism, detoxification, and immune regulation, is particularly vulnerable in this context. Sepsis-induced liver injury (SILI), a frequent and severe complication, markedly worsens clinical outcomes. A growing body of evidence implicates mitochondrial dysfunction as a central pathogenic hub in SILI. During sepsis, mitochondria exhibit profound derangements, including morphological abnormalities, collapse of the membrane potential, respiratory chain failure, excessive reactive oxygen species (ROS) generation, altered dynamics, and defective mitophagy. Beyond intrinsic cellular injury, these dysfunctional organelles can amplify systemic inflammation by releasing damage-associated molecular patterns (DAMPs), which in turn activate innate immune pathways mediated by Toll-like receptors (TLRs), NOD-like receptors (NLRs), and the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis. This review provides an integrative overview of the current understanding of mitochondrial dysfunction in SILI. We critically evaluate preclinical advances in mitochondrial-targeted therapies and highlight emerging strategies that hold translational promise for mitigating hepatic injury and improving patient outcomes.