LPA₃ signaling and biological functions: from physiological regulation to disease-targeted therapy.

Lysophosphatidic acid receptor 3 (LPA₃), a critical member of the G protein-coupled receptor (GPCR) family, plays a central role in maintaining physiological homeostasis and regulating pathological processes by modulating multiple key signaling pathways. Upon activation, LPA₃ triggers several downstream cascades, including Gαq/11, Gαi/o, and Gα12/13, thereby regulating cellular proliferation, survival, migration, inflammatory responses, and metabolic balance. LPA₃ is widely expressed in adipose tissue, the reproductive system, and the nervous system, where it exhibits tissue-specific functions. Recent studies have revealed that aberrant LPA₃ signaling is closely associated with tumorigenesis and metastasis, obesity and insulin resistance, neuroinflammation, and liver diseases. Mechanistically, LPA₃ promotes tumor cell proliferation via the PI3K/Akt and MAPK/ERK pathways, regulates glucose and lipid metabolism through the cAMP/PKA and AMPK axes, and mediates immune and inflammatory responses via NF-κB and the NLRP3 inflammasome. These multifaceted roles indicate that LPA₃ is not only an important physiological regulator but also a potential therapeutic target and biomarker. Future development of selective antagonists, biased ligands, and tissue-targeted delivery systems may enable precision interventions for cancers, metabolic disorders, and neurological diseases. This review systematically summarizes the metabolic pathways, signaling mechanisms, and physiological functions of LPA₃ and discusses its translational potential in disease therapy.