The endocannabinoidomes: pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets

The endocannabinoid system (eCB) is a complex signaling network discovered in mammals during the 1980s-1990s. It conventionally revolves around two arachidonic acid-derived mediators, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol; their main receptors, the cannabinoid receptors of type 1 (CB1) and type 2 (CB2), and the transient receptor potential vanilloid-1 channels; and the enzymes responsible for their biosynthesis and degradation. However, drawing on these discoveries, numerous eCB-like signaling lipids beyond the classical eCBs, have been unveiled, together with their receptors and metabolic enzymes, thus forming a more complex signaling network known as the endocannabinoidome (eCBome). This review explores the physiology, pharmacological complexity, and molecular targets of the mammalian eCBome, highlighting its versatility and redundancy in the context of global health. Emerging mediators, metabolic pathways and mechanisms, receptors, and their implications in human physiology and pathology are described, particularly concerning metabolic disorders, pain, inflammation, neurodegenerative diseases, and cancer. The importance of other "eCBomes" in nonmammalian forms of life that constitute the external and internal environments of mammals is also discussed for the first time in this context. The overarching objective of this article is to gain insights into the potential of eCBome-based therapeutic strategies aimed at enhancing both human and environmental well-being. SIGNIFICANCE STATEMENT: Lipid-based signaling molecules are ubiquitous in nature, yet their study remains challenging due to intricate regulatory mechanisms. Among lipid signaling pathways, the endocannabinoid (eCB) system and its extended version, the endocannabinoidome (eCBome), are particularly remarkable. Comprising hundreds of mediators, and dozens of receptors and metabolic enzymes, the eCBome regulates critical physiological processes not only in mammals but also across diverse organisms, including plants, fungi, and bacteria. This article examines the evolutionary and functional diversity of eCBomes and highlights their untapped potential as multikingdom therapeutic targets to address pressing challenges in global health.