Ch25h/25HC axis orchestrates phagocytosis and lipid metabolism after intracerebral haemorrhage

Abstract Intracerebral haemorrhage (ICH) is a devastating form of stroke for which therapies are lacking. Secondary brain injury driven by erythrocyte lysis contributes to poor outcomes, highlighting the need to enhance endogenous haematoma clearance. Here, we identify cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25HC) as key regulators of phagocytic and lipid-handling responses after ICH. CH25H expression was increased in postmortem human ICH tissue and a mouse ICH model, localising predominantly in perihaematomal phagocytes. Ch25h deficiency in mice exacerbated blood-brain barrier disruption, iron deposition, and neurological deficits after ICH. Conversely, 25HC treatment improved functional recovery and reduced tissue pathology. Single-cell RNA sequencing revealed selective upregulation of Ch25h in activated microglia after ICH, which modulated phago-lysosomal and lipid metabolic gene expression. Consistently, 25HC enhanced erythrocyte phagocytosis and limited lipid droplet accumulation in vitro. Together, these findings identify CH25H/25HC-dependent lipid reprogramming as a critical determinant of phagocyte function and neurological recovery after ICH.