Evaluating FABP5 as a Therapeutic Target for Pain Management

ABSTRACT Background and Objective Fatty acid‐binding proteins (FABPs) are intracellular lipid transporters. Pharmacological inhibition of FABP5 is analgesic in preclinical visceral, inflammatory, neuropathic and joint pain models. Genetic knockout or knockdown of FABP5 induces analgesia in select visceral and inflammatory pain models. This review explores the current evidence supporting FABP5 modulation in pain. Databases and Data Treatment We searched PubMed (January–August 2025) for studies relating to FABP5 modulation in pain. We used terms associated with inhibition, genetic ablation, analgesia, pain behaviours, pain models and associated signalling pathways. Results FABP5 inhibition mediates analgesia through various lipid‐signalling receptors (cannabinoid receptor type 1 [CB 1 ], peroxisome proliferator–activated receptor alpha [PPARα] and transient receptor potential cation channel subfamily V member 1 [TRPV1]). FABP5 inhibitors upregulate N ‐acylethanolamines and various other N ‐acyl amino acids. FABP5 inhibitors also suppress cytokines, chemokines and other inflammatory pathways such as tumour necrosis factor (TNF), interleukin (IL)‐1β, IL‐6, prostaglandin (PG) E 2 and microsomal PG E synthase‐1 (mPGES‐1). We recently found that the potent, peripherally selective, FABP5 inhibitor ART26.12 showed a no observable adverse effect level of 1000 mg/kg/day in rats and dogs. FABP5 inhibition may offer a favourable safety profile when compared to currently prescribed pain medications (e.g., opioids, corticosteroids and anticonvulsants). Conclusions Whilst preclinical data support the potential of FABP5 inhibitors as novel analgesics, further research into sex differences and chronic dosing in visceral and inflammatory pain models is warranted. Despite this, FABP5 inhibition may hold promise for non‐opioid and non‐steroidal management of painful conditions. Significance Statement This review highlights fatty acid–binding protein 5 (FABP5) inhibition as a novel, non‐opioid and non‐steroidal analgesic strategy with multiple mechanisms of action, broad efficacy in preclinical pain models, and a favourable safety profile. FABP5 inhibition may offer promise for the treatment of complex painful conditions.