Metabolic Reprogramming Associated with Ferroptosis Protection by an Indole-Based Antioxidant in Aβ(25-35)-Treated...

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Ferroptosis links iron dysregulation, oxidative stress, and neurodegeneration in amyloid pathologies.
• Compound 20 previously showed antioxidant and neuroprotective properties.

Purpose of the Study:

• Investigate Compound 20's molecular mechanisms against amyloid-beta (Aβ(25-35))-induced ferroptosis.
• Elucidate Compound 20's effects on cellular homeostasis and key molecular pathways.

Main Methods:

• Utilized human neuroblastoma SH-SY5Y cells exposed to Aβ(25-35).
• Assessed ferroptosis markers: glutathione levels, labile iron pool, lipid peroxidation, and mitochondrial membrane potential.
• Analyzed endoplasmic reticulum (ER) stress markers and gene expression via real-time PCR.
• Performed untargeted 1H-NMR metabolomic profiling for systems-level analysis.

Main Results:

• Compound 20 counteracted Aβ(25-35)-induced ferroptosis by restoring glutathione, depleting iron, and suppressing lipid peroxidation.
• Rescued mitochondrial membrane potential and attenuated ER expansion, preserving cellular homeostasis.
• Real-time PCR confirmed modulation of oxidative stress, ER stress, and inflammatory genes.
• Metabolomic profiling revealed activation of antioxidant pathways and modulation of energy and GABA-related pathways.

Conclusions:

• Compound 20 exhibits multifactorial protective effects against Aβ(25-35)-induced ferroptosis.
• The compound orchestrates metabolic reprogramming, coordinating antioxidant defense, iron homeostasis, and ER stress mitigation.
• These actions collectively enhance neuronal resilience and cellular homeostasis under oxidative stress.