A hypothesis-driven perspective on GLP-1R-β-catenin pathway crosstalk in astrocyte plasticity and endogenous neural repair.

Astrocytes exhibit pronounced, context-dependent plasticity following central nervous system (CNS) injury; however, their capacity for fate remodeling remains constrained by chromatin architecture, lineage-stabilizing signaling networks, inflammatory and metabolic states, and disease context. Canonical Wnt/β-catenin signaling has emerged as a context-sensitive regulator of astrocyte transcriptional competence through modulation of chromatin accessibility, enhancer activation, and progenitor-associated programs. However, Wnt activation alone appears insufficient to induce stable astrocyte-to-neuron conversion and should be interpreted within a broader intracellular signaling network. Glucagon-like peptide-1 receptor (GLP-1R) agonists, including exendin-4, exert neuroprotective, anti-inflammatory, and metabolic effects in neurological disease models. GLP-1R activation engages PI3K/Akt and cAMP/PKA signaling, which may intersect with regulatory mechanisms controlling β-catenin stability and transcriptional activity. However, many GLP-1R-mediated effects can also be explained through β-catenin-independent mechanisms involving inflammatory regulation, mitochondrial homeostasis, neurotrophic support, and cellular stress responses. We propose that exendin-4 may function as a permissive modulator rather than a deterministic driver of astrocyte fate remodeling. Importantly, this framework is derived predominantly from indirect evidence, may involve astrocyte-autonomous or non-autonomous mechanisms, and currently lacks direct astrocyte-specific validation. Future studies integrating receptor-expression mapping, pharmacokinetic assessment, lineage tracing, single-cell and spatial multi-omics, epigenomic profiling, and functional analysis will be essential to determine whether pharmacological modulation of permissive signaling states can contribute to endogenous neural repair.