# Circulating adipocyte fatty acid-binding protein exacerbates LPS-induced neurotoxicity by crossing the disrupted blood–brain barrier and promoting neuronal apoptosis

## TL;DR

A protein from fat cells worsens brain damage in sepsis by crossing a leaky blood-brain barrier and causing neuron death.

## Contribution

A-FABP is identified as a novel mediator linking peripheral inflammation to CNS damage in sepsis.

## Key findings

- A-FABP crosses the disrupted blood-brain barrier and accumulates in hippocampal neurons.
- A-FABP synergizes with LPS to promote neuronal apoptosis.
- Neutralizing A-FABP with an antibody reduces BBB dysfunction and neuroinflammation.

## Abstract

Sepsis-associated encephalopathy (SAE) is a critical complication of systemic inflammation with poorly understood mechanisms. This study identified adipocyte fatty acid-binding protein (A-FABP or FABP4) as a key mediator linking peripheral inflammation to central nervous system (CNS) damage. Using an LPS-induced endotoxemia model in wild-type and Fabp4 knockout (KO) mice, we demonstrated that circulating A-FABP (1) crosses the compromised blood‒brain barrier (BBB), (2) accumulates in hippocampal neurons, and (3) synergizes with LPS to drive neuronal apoptosis. The monoclonal antibody 6H2, which neutralizes A-FABP, significantly alleviated BBB dysfunction, attenuated neuroinflammation, and improved neuronal survival. In vitro studies confirmed that HT22 neurons internalize exogenous A-FABP, which amplifies LPS-induced late apoptosis without affecting early apoptotic pathways. These findings establish circulating A-FABP as both a biomarker and therapeutic target for SAE, revealing a novel periphery-to-CNS inflammatory cascade.

The online version contains supplementary material available at 10.1186/s12964-026-02680-y.