GPR37 and GPR37L1-mediated neuroprotection: mechanisms and drug repurposing strategies for reducing neurological disorders

Neurological disorders such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, ischemic stroke, and neuropathic pain are major causes of long-term disability worldwide. The orphan G protein-coupled receptors GPR37 and GPR37L1 have gained considerable research attention as novel therapeutic targets. These receptors play critical roles in neuroprotection, neuroinflammation and tissue repair. GPR37 is primarily expressed in dopaminergic neurons and oligodendrocytes, whereas GPR37L1 is mainly expressed in astrocytes. These receptors modulate various cellular processes through Gi/o-coupled signaling, ERK/MAPK, and PI3K–Akt pathways. Both GPR37 and GPR37L1 affect neuronal survival, remyelination, oxidative stress, apoptosis, glial activation, and phagocytic clearance. Activation of GPR37 and GPR37L1 by their ligands, including prosaposin-derived peptides, neuroprotectin D1, and osteocalcin, regulates protective signaling and promotes functional recovery in the injured central nervous system. This review highlights recent progress in the cellular mechanisms regulating neuroprotection mediated by GPR37 and GPR37L1. This includes GPR37/GPR37L1 molecular characteristics and ligand signaling, mechanisms of proteostasis, ER stress, anti-apoptotic and survival signaling, modulation of oxidative stress, regulation of neuroinflammation, glial-mediated repair and remyelination, and synaptic and dopaminergic regulation. In addition, repurposed drugs targeting these receptors are also reviewed, along with a discussion on the clinical implications of GPR37/GPR37L1 in reducing neurological disorders. Despite these advances, a unified mechanistic framework linking receptor biology with therapeutic development remains lacking. This review proposes a conceptual framework that integrates receptor signaling, disease mechanisms, and drug repurposing strategies, while highlighting testable hypotheses on convergent neuroprotective pathways that warrant experimental validation. This systematic review was conducted in accordance with the PRISMA 2020 guidelines. By providing a translational perspective, this framework may facilitate biomarker discovery, prioritize therapeutic candidates, and accelerate the clinical development of GPR37/GPR37L1-targeted interventions for neurological disorders.