Liver-specific sustained activation of the LPS/TLR4/NF-κB pathway: from a gut-liver axis hub to cascading extensions in reproductive and neuroinflammation.

The chronic activation of the hepatic lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, which links intestinal dysbiosis, chronic hepatic inflammation, and injury to other organs, is a crucial mechanism of pathogenesis in the gut-liver axis. Intestinal barrier disruption facilitates the transport of LPS to the liver, where it activates the TLR4/NF-κB pathway in hepatic stellate cells and Kupffer cells. As a result, a number of positive feedback loops produce a "chronic inflammatory microenvironment," which fuels liver damage, including that caused by alcoholic liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD). Through systemic circulation, hepatogenic inflammatory mediators and metabolites can penetrate tissue barriers and reach the central nervous system (CNS) and reproductive system. With distinct sex-specific variations, they have been associated, largely in preclinical models, with direct effects on ovarian function, interference with the hypothalamic-pituitary-gonadal (HPG) axis, and an increased risk of adverse pregnancy outcomes. These peripheral mediators may penetrate the blood-brain barrier (BBB) and stimulate microglia, contributing to neuroinflammatory and neurodegenerative alterations. Through this route, which interacts with the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, endoplasmic reticulum stress (ERS), and metabolic reprogramming, it cooperatively promotes inflammatory cascades. Therapeutic strategies aimed at restoring intestinal barrier function, inhibiting hepatic TLR4/NF-κB, and providing anti-inflammatory protection to distal organs may, in preclinical models, attenuate inter-organ inflammatory crosstalk. This review systematically synthesizes the available preclinical and clinical evidence along the proposed pathway of enteric initiation, hepatic inflammatory amplification, and subsequent reproductive and neural injury. We explicitly distinguish evidence derived from human observational studies from that obtained in cellular and animal models, identify key translational gaps, and discuss intervention strategies that remain to be validated in human cohorts.