biostudies-literatureWang ZTsinghua Initiative Scientific Research ProgramNational Natural Science Foundation of ChinaBeijing Natural Science Foundation113687https://www.ebi.ac.uk/biostudies/studies/S-EPMC12554141biostudies-literatureUnknown28(11)Microglia represent critical therapeutic targets in spinal cord injury (SCI), with damage-associated microglia (DAM) playing key roles in neuroinflammation and tissue repair. Through integrated in-silico analysis of single-cell RNA sequencing (scRNA-seq) and microarray datasets, we identified DAM subsets specific to acute SCI characterized by hub genes <i>Fcer1g</i>, <i>Grn</i>, and <i>Gusb</i>. Using a C57BL/6 mouse spinal cord contusion model, we validated increased DAM accumulation post-injury and demonstrated their propensity to transition toward homeostatic microglia (MG2). Eupatilin treatment promoted DAM-to-MG2 differentiation, as confirmed through bulk and scRNA-seq analyses, revealing supportive gene expression changes. These findings establish DAM as functionally distinct microglial populations in acute SCI and identify Eupatilin as a therapeutic agent that facilitates beneficial microglial polarization. This work provides mechanistic insights into microglial dynamics during SCI and suggests targeted modulation of DAM-to-MG2 transitions as a promising therapeutic strategy for promoting inflammation resolution and functional recovery.iScienceEupatilin ameliorates spinal cord injury by inhibiting damage-associated microglia and optimizing the regenerative microenvironment.PMC125541412025702001482301560724218782201521Liu YYang JSu BLuan GYu BYang KWang GWang XMan WMeng ZWang ZZhang PfalseEupatilin ameliorates spinal cord injury by inhibiting damage-associated microglia and optimizing the regenerative microenvironment.Microglia represent critical therapeutic targets in spinal cord injury (SCI), with damage-associated microglia (DAM) playing key roles in neuroinflammation and tissue repair. Through integrated in-silico analysis of single-cell RNA sequencing (scRNA-seq) and microarray datasets, we identified DAM subsets specific to acute SCI characterized by hub genes <i>Fcer1g</i>, <i>Grn</i>, and <i>Gusb</i>. Using a C57BL/6 mouse spinal cord contusion model, we validated increased DAM accumulation post-injury and demonstrated their propensity to transition toward homeostatic microglia (MG2). Eupatilin treatment promoted DAM-to-MG2 differentiation, as confirmed through bulk and scRNA-seq analyses, revealing supportive gene expression changes. These findings establish DAM as functionally distinct microglial populations in acute SCI and identify Eupatilin as a therapeutic agent that facilitates beneficial microglial polarization. This work provides mechanistic insights into microglial dynamics during SCI and suggests targeted modulation of DAM-to-MG2 transitions as a promising therapeutic strategy for promoting inflammation resolution and functional recovery.2025-01-01T00:00:00Z2025 Nov2026-06-05T05:17:55.529Z2026-06-04T03:06:09.095ZS-EPMC125541414114671610.1016/j.isci.2025.113687