Lee, Hye Yeong Lee, Jung Moo Lee, Hye-Lan Park, Jiyeon An, Heeyoung Park, Eun Kyung Hwang, Sae Yeon Yoon, Sol lip Hwang, Gwang Yong Kim, Keung Nyun Nam, Min-Ho Lee, Seung Eun Kang, Hyunji Won, Joungha Jang, Bo Ko Lee, Elijah Hwejin Choi, Sunyeong Park, Mingu Gordon Kim, Sang Wook Park, Ki Duk Lee, Seunghwan Lee, C. Justin Ha, Yoon 2025-10-01T11:04:42Z 2025-10-01T11:04:42Z 2025-09-30 2025-09 2095-9907 https://pubs.kist.re.kr/handle/201004/153311 Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system (CNS) injury. The glial scar has been proposed as a major contributor to this failure in the regenerative process. However, its underlying molecular and cellular mechanisms remain unclear. Here, we report that monoamine oxidase B (MAOB)-dependent excessive gamma-aminobutyric acid (GABA) release from reactive astrocytes suppresses the CNS repair system by reducing brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) expression in severe spinal cord injury (SCI) animal models. Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery. Notably, the selective MAOB inhibitor, KDS2010, facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model. Its dose-dependent effects were further validated in a monkey SCI model. Moreover, KDS2010 demonstrated a tolerable safety profile and dose-proportional pharmacokinetics in healthy humans during a phase 1 clinical trial. This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury. Our findings identify the astrocytic MAOB-GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment. English Nature Publishing Group | Sichuan University Astrocytic monoamine oxidase B (MAOB)–gamma-aminobutyric acid (GABA) axis as a molecular brake on repair following spinal cord injury Article 10.1038/s41392-025-02398-2 1 Signal Transduction and Targeted Therapy, v.10, no.1 Signal Transduction and Targeted Therapy 10 1 Y scie scopus 001570528900003 2-s2.0-105015468819 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article CHONDROITIN SULFATE PROTEOGLYCANS STEM-CELL THERAPY AXON REGENERATION ADVERSE EVENTS BRAIN BDNF MOUSE REACTIVE ASTROCYTES NEUROTROPHIC FACTOR RELEASE