Decoding lysophosphatidic acid signaling in physiology and disease: mapping the multimodal and multinodal signaling networks

Lysophosphatidic acid (LPA) signaling has emerged as a central regulatory axis in both normal physiology and disease, orchestrating diverse cellular processes such as proliferation, survival, migration, immune modulation, and tissue remodeling. Originally identified as a bioactive lipid that regulates smooth muscle contraction and vascular tone, LPA has since emerged as a pleiotropic signaling molecule implicated in multiple physiological systems and a wide spectrum of pathological states. These include cancer, neurodegenerative disorders, cardiovascular and metabolic syndromes, inflammatory conditions, and fibrotic diseases. Elevated LPA levels, overexpression of autotaxin (ATX), and aberrant activation of LPA receptors (LPARs) contribute to disease initiation and progression, positioning the LPA axis as both a diagnostic biomarker and a promising therapeutic target. This review describes the multimodal and multinodal organization of the LPA signaling network, detailing upstream biosynthesis, receptor diversity, and downstream effectors across diverse organ systems. Therapeutic strategies targeting ATX, LPARs, and intracellular mediators are critically assessed, along with a review of ongoing and emerging clinical trials. Furthermore, we introduce a context-aware AI-based neural network model to simulate LPA signaling dynamics, providing a framework for predictive modeling and personalized therapeutic interventions. By integrating mechanistic insights with adaptive computational frameworks, this review positions the LPA axis as a powerful and versatile target for systems biology-guided precision medicine strategies in both health and disease.