Ferroptosis, a novel iron-dependent cell death modality, continues to redefine our understanding of cellular fate beyond classical apoptosis and necrosis. Distinguished by intracellular lipid peroxide accumulation that disrupts membrane integrity, this unique form of demise hinges on the interplay of free intracellular iron, oxygen, and polyunsaturated fatty acids (PUFAs). Recent advances elucidate how intricate biochemical pathways and organellar crosstalk orchestrate ferroptotic execution, regulation, and potential therapeutic modulation, reigniting fervent interest across cellular biology and translational medicine.
At the cellular frontier, the breakdown of membrane homeostasis underpins ferroptotic cell death. Central to this process is Na⁺/K⁺-ATPase, a membrane-bound P-type ATPase that harnesses ATP hydrolysis to maintain ionic gradients—exporting three sodium ions while importing two potassium ions per cycle. Lipid peroxidation profoundly impairs this pump’s function, leading to cytoplasmic sodium overload and osmotic imbalance. Concurrently, mechanosensitive channels such as Piezo1 and transient receptor potential (TRP) channels sense the resultant heightened membrane tension, facilitating influxes of sodium and calcium ions, and concomitant potassium efflux. This ionic dysregulation exacerbates cellular swelling and stress.
Calcium ions play a pivotal dual role by engaging proteins like Charged Multivesicular Body Proteins 5 and 6 (CHMP5 and CHMP6) to mobilize localized membrane repair mechanisms. However, excessive lipid peroxidation inhibits these repair machineries, essentially sealing the cell’s fate through catastrophic membrane rupture and ferroptotic death. This disruption of membrane repair under oxidative stress represents a critical node that could be therapeutically targeted to modulate ferroptosis.
The discovery that levels of polyunsaturated fatty acids dictate ferroptotic sensitivity opens a compelling window into metabolic control of cell fate. PUFAs possess bis-allylic hydrogens with low dissociation energies, rendering them preferential substrates for peroxidation. Consequently, the ratio of PUFAs to more oxidation-resistant monounsaturated fatty acids (MUFAs) determines ferroptosis susceptibility. An increase in MUFAs confers resilience, while PUFA enrichment predisposes membranes to fatal oxidation cascades.
This dynamic lipid landscape is intricately shaped within the endoplasmic reticulum (ER), the cell’s lipid biosynthesis nexus. Key enzyme families such as Fatty Acid Desaturases (FADS1 and FADS2) and Acyl-CoA Synthetase Long-chain family members (ACSL3 and ACSL4) enzymatically desaturate and activate fatty acids, tailoring PUFA and MUFA composition within membrane phospholipids. The ER-mediated remodeling pathways, including the sophisticated Lands cycle for phospholipid acyl-chain editing, further modulate ferroptotic thresholds by balancing pro-ferroptotic PUFA incorporation against MUFA-driven resistance.
Moreover, the ER’s influence extends beyond lipid metabolism. Transcription factors like Sterol Regulatory Element-Binding Proteins (SREBPs), regulated via the PI3K-AKT-mTORC1 signaling axis, orchestrate the expression of desaturases such as Stearoyl-CoA Desaturase 1 (SCD1), facilitating MUFA synthesis to fortify membranes against oxidative injury. This regulatory feedback underscores the ER’s multifaceted role in tuning ferroptotic sensitivity by integrating metabolic inputs and stress signals.
Beyond the ER, organelles such as lipid droplets and peroxisomes exert nuanced influences on ferroptosis. Lipid droplets, traditionally viewed as inert lipid storage, selectively sequester PUFAs away from vulnerable membrane sites, thereby insulating cells against lethal lipid peroxidation. However, this protective role is context-dependent, as seen in certain cancer types where lipid droplet accumulation paradoxically heightens ferroptotic sensitivity through the enrichment of PUFA-containing triacylglycerols.
Peroxisomes complement this metabolic orchestra by synthesizing ether lipids enriched with PUFAs, which integrate into plasma membranes to modulate fluidity and ferroptotic vulnerability. Their ability to generate bioactive lipid species positions peroxisomes as crucial modulators of cell death fate under oxidative duress.
Integral to ferroptosis is the pool of bioavailable intracellular iron, predominantly ferrous (Fe²⁺), that serves as a catalyst for lipid peroxidation via Fenton chemistry. Iron imported through the transferrin-transferrin receptor system is liberated within lysosomal compartments, emphasizing lysosomes’ pivotal role in regulating labile iron availability. Interference with iron uptake or ferritin degradation via autophagy (ferritinophagy mediated by NCOA4) profoundly influences ferroptotic sensitivity, showcasing a sophisticated balance between iron homeostasis and cell survival.
Complementing this, the antioxidant defense system forms a bulwark against ferroptotic demise. Glutathione peroxidase 4 (GPX4), a selenium-dependent enzyme, mitigates lipid hydroperoxides by converting them into innocuous lipid alcohols, relying heavily on glutathione (GSH) and selenium availability. The xc⁻ cystine-glutamate antiporter system ensures cystine uptake to maintain GSH synthesis, while lysosomal pathways facilitate protein-derived cysteine liberation. Notably, parallel sulfur metabolites such as coenzyme A furnish additional layers of protection against lipid peroxidation, revealing a complex network of antioxidant redundancy.
Selenium’s integral incorporation into GPX4 is tightly regulated, with specialized transport mechanisms and unique tRNA-dependent selenocysteine biosynthesis pathways. Dietary selenium uptake via selenoprotein P endocytosis and intracellular utilization is crucial; deficiencies manifest as impaired GPX4 expression and heightened ferroptotic susceptibility. These insights emphasize the importance of micronutrient availability in modulating redox balance and cell fate.
Beyond enzymatic defenses, radical-trapping antioxidants (RTAs) such as coenzyme Q10 (CoQ10) and vitamin K emerge as vital suppressors of lipid peroxyl radicals. Synthesized predominantly in mitochondria and regenerated by ferroptosis suppressor protein 1 (FSP1) at the plasma membrane, these lipophilic antioxidants abrogate lipid peroxidation and curtail ferroptotic progression. FSP1’s N-myristoylation anchors it to membranes, a critical feature allowing spatially targeted detoxification of harmful radicals.
Nicotinamide adenine dinucleotide phosphate (NADPH) serves as a central electron donor fueling antioxidant regeneration, including glutathione reduction and the recycling of CoQ10 and vitamin K. Enzymes such as Glutathione Disulfide Reductase and FSP1 leverage NADPH, linking cellular metabolic state to ferroptotic resilience. Interestingly, NADPH’s role is dualistic, also donating electrons to NADPH oxidases and cytochrome P450 enzymes that generate reactive oxygen species (ROS), implicating a delicate balance between antioxidant capacity and ROS-mediated lipid peroxidation.
Mitochondria, often termed the cell’s powerhouse, wield paradoxical control over ferroptosis. Depending on cellular context, they can both promote and hinder ferroptotic death. The tricarboxylic acid cycle and respiratory electron transport chain contribute to ROS generation and iron metabolism, influencing ferroptotic thresholds. Mitochondrial enzymes like DECR1 mitigate PUFA pools, conferring protection, while disruption of mitochondrial dynamics and stress signaling modulate ferroptotic sensitivity. These multifaceted roles exemplify mitochondria’s critical function as modulators rather than mere bystanders in regulated cell death pathways.
Similarly, the endoplasmic reticulum perpetuates ferroptosis through NADPH-dependent enzymes such as cytochrome P450 oxidoreductase (POR) and cytochrome b5 reductase (CYB5R1), which produce ROS fostering lipid peroxidation. The mevalonate pathway synthesizes precursors vital for antioxidant molecules like vitamin K and CoQ10, linking cholesterol metabolism intimately with oxidative stress regulation. The ER-resident transcription factor NFE2L1 enhances GPX4 protein stability through post-translational mechanisms, further underscoring the organelle’s centrality in maintaining redox equilibrium.
Collectively, ferroptosis integrates a complex web of lipid metabolism, iron homeostasis, ROS dynamics, and antioxidant defenses orchestrated by organelles including the ER, mitochondria, lysosomes, and lipid droplets. This intricate regulation offers fertile ground for therapeutic innovation across oncology, neurodegeneration, and beyond, as modulating ferroptotic pathways holds promise for novel interventions in diseases marked by deranged cell death.
Unlocking the enigmatic ferroptotic dance invites a holistic perspective, appreciating the biochemical choreography that dictates cellular life or death. As research deepens, targeting this multifactorial process promises to revolutionize treatments, harnessing ferroptosis as a double-edged sword—either to eliminate malignant cells or protect vulnerable tissues from oxidative catastrophe. The future landscape of ferroptosis biology gleams bright, poised at the nexus of fundamental discovery and clinical impact.
Subject of Research: Regulation of ferroptosis through lipid metabolism, iron homeostasis, reactive oxygen species, and antioxidant systems.
Article Title: Regulation of apoptosis, ferroptosis, and pyroptosis mediated by acetylation.
Article References:
Lu, W., Deng, Y., Liu, M. et al. Regulation of apoptosis, ferroptosis, and pyroptosis mediated by acetylation. Cell Death Discov. 12, 15 (2026). https://doi.org/10.1038/s41420-025-02859-1
Image Credits: AI Generated
DOI: 10.1038/s41420-025-02859-1
Keywords: Ferroptosis, lipid peroxidation, polyunsaturated fatty acids, Na⁺/K⁺-ATPase, Piezo1, TRP channels, CHMP proteins, endoplasmic reticulum, iron metabolism, lysosomes, glutathione peroxidase 4, selenium, coenzyme Q10, ferroptosis suppressor protein 1, NADPH, mitochondria, reactive oxygen species, antioxidant enzymes
Tags: Acetylation in cell death mechanismsapoptosis regulation pathwaysbiochemical pathways in ferroptotic executioncalcium ions in cellular stressferroptosis and lipid peroxidationionic dysregulation in cell deathmechanosensitive channels in ferroptosismembrane integrity in cell deathNa⁺/K⁺-ATPase functionorganellar crosstalk in apoptosistherapeutic modulation of ferroptosistranslational medicine in cell biology
