Systematic review links NAE-like compounds to TLR4 inflammation pathways

N-acylethanolamines (NAEs) are endogenous fatty acid amides structurally related to the endocannabinoid anandamide and function as bioactive lipid mediators with broad regulatory roles in inflammation and neuroinflammation. Among pattern-recognition receptors, Toll-like receptor 4 (TLR4) occupies a central position in innate immune surveillance, sensing pathogen-associated molecular patterns, such as lipopolysaccharide (LPS), as well as damage-associated molecular patterns. Upon ligand engagement, TLR4 triggers both MyD88- and TRIF-dependent signaling cascades, leading to NF-κB activation and the transcriptional induction of pro-inflammatory cytokines and Type I interferons. Within this family, classical NAEs, such as palmitoylethanolamide (PEA), and structurally distinct NAE-like derivatives represent two partially overlapping but pharmacodynamically different groups of bioactive compounds. Classical NAEs, including palmitoylethanolamide (PEA), primarily exert their anti-inflammatory actions through activation of peroxisome proliferator-activated receptors and related nuclear pathways. In contrast, NAE-like compounds with distinct scaffolds, such as 2-pentadecyl-2-oxazoline (C15OXA) and N-palmitoyl-D-glucosamine (PGA), may interact with the TLR4/MD-2 complex and modulate receptor activation more proximally, as suggested by cell-based functional assays and computational modeling. PRISMA-guided analyses across experimental models of colitis, LPS-induced systemic inflammation, and alcohol binge exposure consistently demonstrate the anti-inflammatory efficacy of PGA and C15OXA, identifying TLR4 as a pivotal mechanistic node underlying their activity. Together, these findings delineate distinct yet partially convergent pharmacodynamic profiles among endogenous NAEs and naturally occurring NAE-like compounds, supporting their potential relevance as natural-product-inspired pharmacological strategies for the modulation of TLR4-associated inflammatory and neuroinflammatory processes.