CTSS regulates macrophage lipid metabolic reprogramming and white matter repair after intracerebral hemorrhage

作者：Xian Yu, Huaping Huang, Dandan Mao, Jianmin Wu, Jiahe Pan, Yirui Kuang, Yiwen Wu, H H Chen, Linfeng Fan, Yonghe Zheng, Jiayin Zhou, Shandong Jiang, Xinyan Wu, H J Zhou, W Yan, Haiyan Zheng, Jingyin Chen, Gao Chen, Chi Gu · 发表于：Journal of Translational Medicine · 年份：2026 · DOI：10.1186/s12967-026-08523-1 · 研究领域：Intracerebral and Subarachnoid Hemorrhage Research、Neuroinflammation and Neurodegeneration Mechanisms、Immune cells in cancer

BACKGROUND: Intracerebral hemorrhage (ICH) causes secondary white matter injury, which contributes substantially to long-term neurological disability. Although macrophages accumulate in the perihematomal region and participate in tissue remodeling after ICH, the molecular programs that link macrophage responses to white matter repair remain poorly understood, and no current strategies specifically target macrophage‑mediated white matter restoration. Cathepsin S (CTSS), a lysosomal cysteine protease involved in immune regulation and tissue remodeling, is strongly induced after brain injury; however, its role in post‑ICH white matter pathology has not been defined. METHODS: A collagenase-induced mouse model of intracerebral hemorrhage (ICH) was established, followed by pharmacological inhibition of Cathepsin S (CTSS) using LY3000328. Single-cell RNA sequencing was performed on perihematomal tissues from Vehicle- and CTSS inhibitor-treated mice to explore CTSS-responsive cell populations and transcriptional programs. Macrophage lipid handling was assessed using flow cytometry, immunofluorescence, and fluorescent myelin debris-based uptake and lipid-transfer assays. A bone marrow-derived macrophage (BMDM)-oligodendrocyte precursor cell (OPC) co-culture system was used to determine whether CTSS inhibition alters macrophage-derived lipid support for OPC differentiation. The LXR agonist GW3965 was applied as a rescue intervention. White matter repair and neurological recovery were e...