Hepatic Orosomucoid 2 aggravates demyelination and drives microglial DAM-like activation

Demyelination is a central pathological feature of white matter injury (WMI). Emerging evidence suggests that hepatokines act as systemic regulators of brain pathology, raising the possibility that liver-derived signals contribute to WMI. Here, we investigated whether hepatokine Orosomucoid 2 (ORM2) aggravates demyelination through liver-brain communication by modulating disease-associated microglia (DAM)-like activation in WMI. ORM2 expression was assessed in the cuprizone (CPZ) demyelination model using RNA sequencing, quantitative PCR, western blotting, and immunofluorescence. The functional role of ORM2 in WMI was examined using ORM2 knockout mice, hepatocyte-specific ORM2 transgenic mice, and hepatocyte-targeted ORM2 knockdown strategies, combined with behavioral analyses and histological evaluation of myelin integrity. Transcriptomic profiling, lipid staining, and microglial phenotyping were performed to characterize DAM-associated responses. CPZ-induced demyelinating challenge was accompanied by robust hepatic ORM2 induction and increased cerebral ORM2 protein accumulation. Flag-tagged ORM2 tracing showed that hepatocyte-derived ORM2 could be detected in the injured brain after CPZ-induced white matter injury. ORM2 deficiency alleviated, whereas hepatocyte-specific ORM2 overexpression exacerbated, demyelination and behavioral deficits. Hepatocyte-targeted knockdown of ORM2 reduced cerebral ORM2 accumulation and mitigated white matter pathology, supporting a peripheral contribution of hepatic ORM2 to WMI. Transcriptomic and histological analyses revealed that ORM2 promoted inflammatory and DAM-like microglial programs. Mechanistically, ORM2 promoted activation of the SYK-PLCγ2 signaling axis, thereby driving DAM-like activation, lipid-associated dysregulation, and myelin loss. Our findings identify hepatic ORM2 as a pro-inflammatory hepatokine that aggravates WMI through liver-brain communication. By enhancing SYK-PLCγ2 signaling and driving DAM-like microglial activation, ORM2 links peripheral hepatic stress to central demyelination, highlighting hepatic ORM2 as a potential therapeutic target for white matter disorders.