Abstract
BACKGROUND: Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an index of ferroptosis. Here, serum ACSL4 levels were examined to determine their prognostic significance and mediating roles in patients with acute intracerebral hemorrhage (ICH). METHODS: In this observational analytical study, serum ACSL4 levels were measured at admission in 317 patients with supratentorial intraparenchymal hemorrhage and at study entry in 100 controls. The National Institutes of Health Stroke Scale (NIHSS) score and hematoma volume were used as the severity metrics. Poor prognosis was designated as modified Rankin Scale (mRS) 3-6 at six months following ICH. Stroke-associated pneumonia (SAP) was defined as an acute lower airway infection within a week post-ICH. The outcome variables of interest were SAP and poor prognosis. Multifactorial means were implemented for severity and outcome analyses. RESULTS: Patients had significantly higher serum ACSL4 levels than controls. Serum ACSL4 levels remained linearly connected with NIHSS scores, hematoma volume, SAP, mRS scores, and poor prognosis under restricted cubic spline and kept substantially associated with them even after adjusting for other confounding factors. The independent associations with poor prognosis and SAP were robust via sensitivity analysis, and exhibited no interactions with age, sex, tobacco smoking, and others through subgroup analysis. Regarding the predictive ability for poor prognosis and SAP under the receiver operating characteristic curve, serum ACSL4 levels were statistically comparable to the NIHSS scores and hematoma volume. Using mediation analysis, serum ACSL4 levels partially mediated the associations of NIHSS scores and hematoma volume with poor prognosis and SAP, and SAP in part mediated the relationship between serum ACSL4 levels and mRS scores plus poor prognosis. CONCLUSION: Enhanced serum ACSL4 levels post-ICH are significantly linked to ICH severity and clinical outcomes, and serum ACSL4 may partially interpret outcome associations, therefore extrapolating serum ACSL4 as a prognostic adjunct of ICH.