Intracerebral hemorrhage (ICH) is associated with the highest rates of mortality and residual disability. To date, effective treatments to delay or prevent ICH are still lacking. Multiple forms of neuronal cell death have been discovered following ICH, including apoptosis, necrosis, autophagy, and ferroptosis. Aldo-keto reductase family 1 member C1 (AKR1C1) has been identified to act as a protective factor in ferroptosis. However, whether AKR1C1 was involved in the development of ICH was unknown. In this study, the left cerebral striatum of the Sprague-Dawley rat was injected with collagenase type IV to induce an in vivo model. Primary rat cortical neurons treated with oxygen hemoglobin (OxyHb) were applied to as an in vitro model. AKR1C1 was found to be downregulated and immunoreactivity colocalized with NeuN-positive neurons in the perihematomal region. Rats injected with lentiviral particles overexpressing AKR1C1 showed the reduction of cerebral hematoma and the remission of blood-brain barrier disruption. Moreover, AKR1C1 upregulation repressed cell apoptosis and ferroptosis induced by ICH through downregulating the expression of pro-apoptotic factors, inhibiting iron accumulation and lipid peroxidation, along with increasing the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). The results of in vitro assays were consistent with results from the in vivo . Mechanistically, P53 overexpression augmented the cellular damage in OxyHb-stimulated neurons when AKR1C1 was overexpressed. Taken together, AKR1C1 improves ICH injury by inhibiting neuronal cell death via negatively regulating P53 expression and affecting the SLC7A11/GPX4 pathway.
Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, in which ferroptosis is a key pathogenic mechanism. This study examines how alpha-linolenic acid (ALA), a plant-derived omega-3 polyunsaturated fatty acid, protects against damage from ferroptosis in DCM. Using an in vitro model of H9C2 cardiomyocytes treated with high glucose/palmitate, combined with a high-fat diet and mouse model of low-dose streptozotocin (STZ)-induced diabetes, this research demonstrates for the first time that ALA significantly alleviates cardiac dysfunction and prevents ferroptosis. Mechanistically, ALA inhibits STAT3 phosphorylation by activating the AMPK signaling pathway, thereby reducing NCOA4-mediated ferritinophagy and mitigating mitochondrial iron overload and reactive oxygen species accumulation. It also enhances the function of the SLC7A11/GSH/GPX4 axis, reducing lipid peroxidation (LPO)-induced ferroptosis. Collectively, these findings indicate that ALA protects against diabetic cardiomyopathy by coordinating the regulation of ferritinophagy and antioxidant defense through the AMPK-STAT3 pathway, offering a potential therapeutic strategy for disease management.
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