Biogerontology · Oct 24, 2026

Pharmacological downregulation of Fetuin-A attenuates TLR4-mediated neuroinflammation in aged rats with minimal hepatic encephalopathy

By Singh VV, Thakur P, Prasad SK et al.

Minimal hepatic encephalopathy (MHE) is a neurological complication associated with chronic liver disease characterized by subtle cognitive impairment and neuroinflammation, particularly in the aging population. However, the molecular mechanisms underlying age-associated MHE remain poorly understood. The present study investigated the role of Fetuin-A-mediated neuroinflammation and its potential as a therapeutic target in the management of MHE in old rats using pioglitazone in a thioacetamide (TAA)-induced MHE model in aged rats. Old male rats were administered TAA (50 mg/kg) for 14 days to induce MHE, followed by pioglitazone treatment (3 mg/kg) for 7 days. Western blot and immunofluorescence analyses revealed elevated hippocampal Fetuin-A expression in MHE rats, accompanied by activation of the TLR4/MyD88/NF-κB signaling pathway and increased inflammatory cytokines (IL-6 and TNF-α). Pioglitazone treatment significantly reduced Fetuin-A expression and was accompanied by reduced TLR4, MyD88 and nuclear NF-κB expression, and by decreased astrocyte activation Furthermore, histological and Golgi-Cox analyses demonstrated restoration of neuronal density, dendritic arborization, and spine density in the hippocampus of pioglitazone-treated old MHE rats. Behavioral analyses further confirmed the molecular and histological findings. Thus, elevated hippocampal Fetuin-A is associated with TLR4/MyD88/NF-κB activation in aged MHE rats, and its pharmacological reduction by pioglitazone is accompanied by reduced neuroinflammation, restored hippocampal cytoarchitecture and recovered recognition memory. A causal role for Fetuin-A remains to be established by direct perturbation.

doi.org/10.1007/s10522-026-10533-xPubMed 42925439Interventions