A Novel Bioactive Component, Efoba, From Aged Garlic Targets CTSC to Suppress NET‐Driven Neuroinflammation and Ameliorate Secondary Brain Injury After Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating neurological disorder with high mortality and disability, where neuroinflammation-driven secondary brain injury is a key pathological hallmark. Neutrophil extracellular traps (NETs) serve as critical pathogenic mediators that amplify neuroinflammation, disrupt blood-brain barrier integrity, and exacerbate brain damage after ICH. This study identifies Efoba, a novel bioactive monomer from aged garlic, and establishes a scalable total‑synthesis route for hundred‑gram‑scale high‑purity production, overcoming low‑yield and supply‑limiting bottlenecks for natural product research. In vivo and in vitro experiments show Efoba markedly ameliorates ICH‑induced neurological impairments and inhibits NET formation. Integrative analyses (Lip-MS, virtual screening, proteomics, transcriptomics) identified cathepsin C (CTSC) as the direct binding target of Efoba. Efoba stabilizes microglial lysosomal membranes, inhibits CTSC release, blocks NET generation, and exerts neuroprotection against NETs-driven neuroinflammation. CTSC knockout and CTSC overexpression assays further confirm the indispensable role of CTSC in mediating Efoba's neuroprotective and anti‑inflammatory activities. Collectively, this work demonstrates for the first time that Efoba targets CTSC to suppress NET-mediated neuroinflammation, highlighting its therapeutic potential and the translational value of natural active components.