Lipids are versatile molecules with different chemical structures and properties, and researchers have harnessed the properties of lipids to create drugs and drug delivery systems for different therapeutic purposes. Cyclic phosphatidic acid (cPA) is a unique phospholipid with a cyclic structure. This cyclic ring differentiates it from typical linear phosphatidic acids including lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA)
[47][48]. The first cPA family member was originally isolated from slime mold and designated as physarum lysophosphatidic acid
[49]. Several cPA activities have been attributed to albumin-associated lipid factors. Autotaxin (ATX) was initially identified as an enzyme secreted by cancer cells and found to stimulate cell motility, i.e., “taxis”
[50]. cPA generation by autotaxin (ATX) under nonphysiological conditions was first reported in 2006
[51]. ATX is a lysophospholipase D and converts LPC into LPA
[52][53][54]. LPA is a bioactive lipid that plays a role in inflammation
[55]. ATX and the LPA it generates are involved in several physiological and pathological processes, including inflammation, angiogenesis, fibrosis, and cancer progression
[56][57][58][59]. LPA is a potent chemoattractant that can attract immune cells, such as neutrophils and monocytes, to sites of inflammation
[60]. This is important for the immune response against infections or tissue damage. Thus, ATX in LPA production can contribute to the recruitment of immune cells to inflamed tissues
[61]. LPA can also stimulate the production of pro-inflammatory cytokines, such as IL-6 and TNF-α, by immune cells. These cytokines further amplify the inflammatory response. Excessive LPA signaling can lead to fibrosis, which is the formation of excess fibrous connective tissue
[62]. Fibrosis is characterized by excessive accumulation of ECM proteins, e.g., collagen, in tissues, leading to tissue scarring and dysfunction
[63][64]. This can occur in various organs and impair their function. LPA can induce fibrosis-associated inflammation
[65]. Inflammatory cells, such as macrophages, can release LPA, and LPA, in turn, can recruit and activate immune cells, perpetuating the inflammatory response and contributing to fibrosis
[66]. The signaling pathways triggered by LPA are complex and can have both pro-inflammatory and pro-survival effects
[67]. Because of their involvement in various diseases, particularly cancer and inflammatory conditions, ATX and LPA have been investigated as potential therapeutic targets for OA. By inhibiting ATX, these inhibitors decrease LPA levels in the body, which can have therapeutic effects in certain medical conditions. ATX inhibitors have been explored as potential treatments for conditions such as fibrosis, cancer, and autoimmune diseases involving dysregulated LPA signaling
[68]. The development of ATX inhibitors is an active area of research. Several compounds with inhibitory activity against ATX have been investigated in preclinical and clinical studies
[69]. These inhibitors can be small molecules or biologics designed to disrupt the enzymatic activity of ATX or its interactions with its substrates
[70]. cPA is also a physiological constituent of human serum
[71]. Its stability allows cPA to function as a bioactive lipid mediator in various physiological processes
[72]. cPA shows several unique actions compared with those of LPA. cPA inhibits cell proliferation, whereas LPA stimulates cell proliferation, migration, and differentiation
[73]. cPA suppresses cancer cell invasion and metastasis by inhibiting ATX and transient activation of low-molecular-weight GTPases and RhoA
[74]. Additionally, cPA can modulate ATX activity, affecting LPA levels
[75] and, consequently, inflammation
[76][77]. However, it is important to note that the metabolic stability of cPA can vary depending on factors such as the specific tissue or cell type, presence of enzymes or other molecules that may degrade it, and the local microenvironment. cPA has been implicated in various cellular processes and has important roles in cell signaling, cell growth, and differentiation
[78][79][80][81][82][83]. It acts as a potent signaling molecule in various physiological contexts. The synthesis of cPA is tightly regulated, and its levels can be influenced by various cellular signals and stimuli. For example, certain growth factors, hormones, and neurotransmitters can modulate the activity of glycerophosphodiesterase 7 (GDE7) and thus affect cPA levels in the cell
[84]. GDE7 suppresses the peroxisome proliferator-activated receptor gamma (PPARγ) pathway, suggesting that cPA functions as an intracellular lipid mediator. PPARγ is a type of nuclear receptor protein that plays a crucial role in regulating gene expression and is primarily involved in the control of lipid metabolism and glucose homeostasis
[85].
Moreover, 2carba-cyclic phosphatidic acid (2carba-cPA) is a modified form of cPA
[86], in which the phosphate group in cPA is replaced with a carba linkage, a carbon-carbon bond. This modification eliminates the negative charge typically associated with the phosphate group in cPA and can considerably affect the properties of a molecule and its biological activities
[75][87][88][89][90]. One of the key features of 2carba-cPA is its enhanced stability compared to natural cPA. This stability allows it to persist longer in biological systems, making it a valuable tool for research and potential therapeutic applications. Like natural cPA, 2carba-cPA can interact with specific receptors, including G protein-coupled receptors (GPCRs), and initiate intracellular signaling cascades
[91]. It may modulate various cellular processes, including cell proliferation, migration, and calcium signaling, depending on the cell type and receptor subtype involved. Research suggests that 2carba-cPA may have anti-cancer properties
[91]. Preclinical studies have shown that 2carba-cPA inhibits the growth and metastasis of cancer cells. The stability and ability of 2carba-cPA to interfere with cancer cell signaling pathways make it a potential candidate for cancer therapy research. Some studies indicate that 2carba-cPA may have neuroprotective effects
[88]. Therefore, its ability to protect neurons and potentially mitigate neurodegenerative diseases could be further explored. Some studies have shown the anti-inflammatory properties of 2carba-cPA
[92], indicating its potential to modulate immune responses and inflammation-related diseases
[93]. Research suggests that 2carba-cPA may play a role in metabolic regulation, including the control of lipid metabolism and glucose homeostasis, which could have implications for the treatment of metabolic disorders like diabetes and obesity. Due to its stability and promising biological activities, 2carba-cPA is a candidate for therapeutic development that may be used in drug discovery and development for conditions such as cancer, neurodegenerative diseases, inflammation-related disorders, and metabolic disorders.