Cerebral ischemia/reperfusion (I/R) may aggravate tissue injury by promoting oxidative stress, inflammation and cell death after ischemic injury. This study aimed to identify cerebral I/R-associated hub genes and to reveal the underlying mechanism on ischemic I/R. Differential expressed genes (DEGs) were identified from the Gene Expression Omnibus (GEO) database, and hub genes were screened from a protein-protein interaction (PPI) network. The I/R rat model was constructed using the middle cerebral artery occlusion and reperfusion (MCAO/R), and Hmox1 was silenced to investigate its effects on I/R injury, inflammation, oxidative stress and ferroptosis. The effects of silencing Hmox1 were also evaluated in OGD/R-treated HT22 cells. The inhibitor of peroxisome proliferator-activated receptor (PPAR)-γ pathway, T0070907, was used to determine the regulation of Hmox1 on the PPAR-γ/fatty acid binding protein 4 (FABP4) pathway. Heme oxygenase 1 (Hmox1), matrix metalloproteinase-13 (Mmp13), CD44 molecule (Cd44), C-C motif chemokine ligand 3 (Ccl3) and serpin family B member 5 (Serpinb5) were selected as hub genes with higher expression in MCAO/R rats. Silencing Hmox1 inhibited cell apoptosis, decreased tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), IL-6, Fe, malondialdehyde (MDA) and reactive oxygen species (ROS), but increased glutathione (GSH). Silencing Hmox1 suppressed the expression of cyclooxygenase 2 (COX2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) but promoted glutathione peroxidase 4 (GPX4) expression, with the upregulation of PPAR-γ and FABP4. Application of T0070907 reversed the effects of silencing Hmox1. Silencing Hmox1 ameliorated cerebral injury, inflammation and ferroptosis via the PPAR-γ/FABP4 pathway, offering theoretical basis for cerebral I/R management. 2+
