Fatty Acid Binding Protein 4 (FABP4): a Key Player in Neuroinflammation and Neuropathic Pain

Free Radic Biol Med. 2026 Feb 26:S0891-5849(26)00169-3. doi: 10.1016/j.freeradbiomed.2026.02.066. Online ahead of print.

ABSTRACT

Neuropathic pain (NP) is caused by lesions or diseases of the somatosensory system. Emerging evidence implicates adipokines in NP pathogenesis, yet the role of fatty acid-binding protein 4 (FABP4) remains unclear. Using a mouse model of sciatic nerve crush injury, we found that wild-type (WT) mice developed robust NP behaviors, concomitant with significant FABP4 upregulation and extensive macrophage infiltration in the injured nerve. In contrast, FABP4-knockout (FABP4-KO) mice exhibited markedly attenuated pain hypersensitivity. Single-cell RNA sequencing and subsequent histological analyses revealed that FABP4 deficiency diminished inflammatory responses and significantly reduced the infiltration of pro-inflammatory M1 macrophages at the lesion site. Crucially, preemptive pharmacological inhibition of FABP4 in WT mice recapitulated this protective phenotype, mitigating both pain and neuroinflammation. Mechanistic studies in vitro demonstrated that FABP4 promotes macrophage pro-inflammatory polarization via activation of the NF-κB pathway. Collectively, our findings identify FABP4 as a novel key contributor to NP by driving macrophage-mediated neuroinflammation, highlighting its potential as a therapeutic target for pain control.

PMID:41763498 | DOI:10.1016/j.freeradbiomed.2026.02.066