Toll‐Like Receptor 4 Signaling in Natural N‐Acylethanolamines and Derivative NAE ‐Like Compounds: Mechanisms and Implications for Neuroimmune and Inflammatory Processes in a Systematic Search Approach

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.