Hepatic Immunometabolic Reprogramming during Systemic Infections: Cellular Pathways Linking Innate Immunity and Metabolic Stress

Carlo Acierno^1,*, Flavia Carriero², Alfredo Caturano³, Valentina Rubino⁴, Ferdinando Carlo Sasso⁵, Salvatore D’Angelo^2,6, Luca Rinaldi⁷, Giuseppe Terrazzano²
1 Department of Infectious Diseases, San Carlo Hospital, Potenza, Italy
2 Department of Health Sciences, University of Basilicata, Potenza, Italy
3 Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma University, Rome, Italy
4 Dipartimento di Scienze Mediche Traslazionali, Università di Napoli Federico II, Napoli, Italy
5 Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Napoli, Italy
6 Rheumatology Department of Basilicata, San Carlo Hospital, Potenza, Italy
7 Department of Medicine and Health Sciences “Vincenzo Tiberio”, Università degli Studi del Molise, Campobasso, Italy
* Corresponding Author: Carlo Acierno. Email: email
(This article belongs to the Special Issue: Cellular and Molecular Mechanisms of Gut Microbiota, Oxidative Stress, and Inflammation in Health and Disease)

BIOCELL https://doi.org/10.32604/biocell.2026.085405

Received 11 May 2026; Accepted 23 July 2026; Published online 04 August 2026

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Abstract

Systemic infections expose the liver to convergent microbial, inflammatory, vascular, and metabolic stress signals. This narrative review synthesizes how hepatic immunometabolic reprogramming links innate immune sensing, bioenergetic stress, and sepsis-associated liver injury or dysfunction. It focuses on hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells as a coordinated sinusoidal network rather than isolated cell compartments. Infection-derived pathogen-associated molecular patterns, host-derived damage-associated molecular patterns, cytokines, hypoxia, altered substrate flux, mitochondrial injury, endoplasmic reticulum stress, lipid remodeling, and redox imbalance are integrated into a temporal framework. Early responses may support host defense through acute-phase biosynthesis, microbial clearance, iron restriction, metabolic redistribution, and microvascular coordination. Persistent or spatially disorganized signaling may instead amplify nuclear factor kappa B and inflammasome activation, disrupt adenosine monophosphate-activated protein kinase-mechanistic target of rapamycin-hypoxia-inducible factor 1 alpha balance, impair sinusoidal perfusion, and promote cholestatic, hepatocellular, endothelial, and stromal maladaptation. Pre-existing metabolic dysfunction-associated steatotic liver disease, insulin resistance, aging, sex-related modifiers, and gut-liver axis disruption may lower the threshold for maladaptive trajectories. Evidence-graded biomarkers and clinical phenotypes are therefore framed as hypothesis-generating tools for trajectory-based translational studies.

Keywords

Systemic infection; sepsis-associated liver dysfunction; sepsis-associated liver injury; hepatic immunometabolism; Kupffer cells; liver sinusoidal endothelial cells; hepatic stellate cells; mitochondrial dysfunction; inflammasome; adenosine monophosphate-activated protein kinase

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Hepatic Immunometabolic Reprogramming during Systemic Infections: Cellular Pathways Linking Innate Immunity and Metabolic Stress

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