Activin A in the central nervous system: Mechanistic and therapeutic insights unveiled by emerging technologies

Activin A exhibits both protective and pathological roles in the central nervous system, reflecting a functional duality that complicates its therapeutic development. To decipher the underlying mechanisms responsible for these contradictions, we leverage emerging technologies that establish comprehensive cellular and spatiotemporal contexts for its signaling pathway. These approaches elucidate the mechanisms underlying central nervous system diseases and their potential therapeutic applications. In this review, we demonstrate how these advanced technologies enhance our understanding of the mechanism of activin A: CRISPR-based editing validates critical receptors such as ACVR1B in the process of remyelination; organoid and organ-on-a-chip systems model human-specific cellular interactions; spatial and single-cell multi-omics delineate expression and communication networks; and optogenetics/chemogenetics enable precise spatiotemporal control of signaling pathway activity. This technological toolkit provides a robust framework for elucidating the context-specific roles of activin A in conditions such as ischemic stroke, neurodegenerative diseases, glioma, epilepsy, and traumatic brain injury, encompassing key processes including neuroprotection, inflammation, and repair. Furthermore, these mechanistic insights inform next-generation interventions, including adeno-associated virus-mediated gene therapy for localized modulation and advanced nanodelivery systems for targeted biologic transport. Given these capabilities, artificial intelligence plays a crucial role in designing blood-brain barrier-permeable ligands and optimizing smart nanocarriers. By contrasting preclinical data with the clinical pipeline, which currently emphasizes peripheral diseases, we propose that integrating mechanism-decoding technologies with artificial intelligence-engineered delivery platforms is a critical pathway for advancement.