Summary
Cardiovascular disease is the global leading cause of death and expresses the same oxidative terminal mechanism observed in neurodegenerative disease. The convergence of iron overload and reactive oxygen species results in lipid peroxidation and ferroptotic cell death within cardiomyocytes and vascular endothelium. Recent findings link this process to heme trafficking and Bach1–HO-1 signaling, where stress induced lipid peroxidation releases free iron from mitochondria associated membranes. This unites excitotoxicity and ferroptosis into a single pathway of redox collapse that applies across brain and heart.
Mechanistic Sequence
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Iron dysregulation and Fenton chemistry
Excess Fe²⁺ reacts with H₂O₂ to form hydroxyl radicals, the most destructive form of ROS (Yan et al., 2022). These radicals oxidize lipids and proteins and damage mitochondrial DNA. HO-1 and TFR1 rise in cardiac tissue during ischemia and heart failure, confirming chronic iron mobilization (Hu et al., 2021). -
Mitochondrial ROS production
Mitochondria both generate and absorb oxidative damage. Calcium influx during ischemia increases oxidative phosphorylation and electron leakage, producing hydrogen peroxide that interacts with Fe²⁺ to generate hydroxyl radicals (Peoples et al., 2019; Yan et al., 2022). -
PGRMC1 and MAM redox coupling
PGRMC1 controls heme export from mitochondria through mitochondria associated membranes, coordinating iron, lipid, and calcium fluxes (Piel et al., 2025). Loss of PGRMC1 causes heme accumulation, free iron release, and lipid peroxidation. This identifies PGRMC1 as a redox gatekeeper that prevents stress induced transition from oxidative metabolism to ferroptotic death. -
Bach1–HO-1 feedback and mitochondrial iron influx
Lipid peroxidation activates Bach1 nuclear export, derepresses HO-1, and drives mitochondrial iron accumulation (Liu et al., 2025). This forms a self-amplifying loop where ROS and iron mutually intensify. Inhibiting HO-1 or blocking mitochondrial Fe²⁺ import rescues cardiac cells, confirming that the HO-1 pathway governs ferroptotic onset. -
GPX4 depletion and GSH loss
Depletion of GPX4 and glutathione disables the antioxidant barrier and allows uncontrolled lipid peroxidation (Hu et al., 2021; Sawicki et al., 2023). -
Lipid peroxidation and ferroptotic rupture
Malondialdehyde and 4-hydroxynonenal accumulate, signaling membrane oxidation and ferroptosis (Yan et al., 2022). ACSL4 facilitates oxidizable lipid synthesis, which amplifies peroxidation until membranes rupture (Hu et al., 2021). -
Inflammation and endothelial activation
Oxidized phospholipids trigger NF-κB and toll-like receptor pathways, producing cytokines that sustain vascular inflammation (Sugamura & Keaney, 2011; Sawicki et al., 2023). -
Tissue failure
The combined effect is cell rupture, fibrosis, and heart failure, identical in molecular logic to excitotoxic neuronal death (Peoples et al., 2019).
Molecular Markers
| Marker | Direction | Function |
|---|---|---|
| HO-1 | ↑ | Releases Fe²⁺ during stress and promotes ferroptosis (Liu et al., 2025) |
| TFR1 | ↑ | Increases iron import during ischemia (Hu et al., 2021) |
| GPX4 | ↓ | Prevents lipid peroxide buildup when intact (Hu et al., 2021) |
| GSH | ↓ | Depleted antioxidant pool (Peoples et al., 2019) |
| ACSL4 | ↑ | Synthesizes oxidizable lipids (Hu et al., 2021) |
| 4-HNE and MDA | ↑ | Mark lipid peroxidation (Yan et al., 2022) |
| PGRMC1 | ↓ | Loss increases ferroptotic sensitivity (Piel et al., 2025) |
| NRF2 | variable | Regulates antioxidant gene induction (Sawicki et al., 2023) |
Therapeutic Insights
- Iron chelation reduces hydroxyl radical formation and prevents reperfusion injury (Yan et al., 2022).
- HO-1 modulation or mitochondrial iron blockade rescues cardiac function (Liu et al., 2025).
- Restoring PGRMC1 activity maintains heme flux and redox balance (Piel et al., 2025).
- NRF2 activation and mitochondrial antioxidants like SS-31 or MitoQ mitigate ROS (Peoples et al., 2019).
Interpretation
CVD and neurodegeneration represent opposite poles of the same redox failure. Chronic stress drives calcium influx and mitochondrial ROS, while lipid peroxidation and HO-1 signaling liberate iron and propagate oxidative injury. PGRMC1 serves as the heme iron checkpoint that regulates this exchange. When stress, iron, and ROS converge, the system enters a ferroptotic loop of self amplifying damage.