Ferroptosis

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. Cancer cells often have higher levels of iron than normal cells, making them more susceptible to ferroptosis.

Metabolism-regulated ferroptosis in cancer progression and therapy {review}

Glucose Metabolism: Glucose is imported into the cell and phosphorylated by HK2 (hexokinase 2) to form G6P (glucose-6-phosphate). G6P can enter the pentose phosphate pathway (PPP) generating NADPH, or continue glycolysis leading to the production of pyruvate.

Pyruvate Metabolism: Pyruvate enters mitochondria where it is converted to Acetyl-CoA by PDH (pyruvate dehydrogenase), feeding into the TCA cycle. The TCA cycle involves conversion of Acetyl-CoA into citrate, followed by transformations into α-KG (α-ketoglutarate), succinic acid, fumaric acid, and finally back to oxaloacetate.

Malate Shuttle: Malic acid is involved in the shuttle converting between NADP+ and NADPH, facilitated by ME1 (malic enzyme 1).

Lipid Peroxidation and Ferroptosis: In the mitochondria, excessive lipid peroxides (PLOOH) can accumulate leading to ferroptosis. Ferroptosis is marked by the accumulation of lipid peroxides and their derivatives (PLOOH, PLOO•).

Antioxidant Defense: GPX4 (glutathione peroxidase 4) reduces lipid peroxides to non-toxic lipid alcohols (PLOH) using GSH (glutathione). GSH is regenerated from GSSG (oxidized glutathione) by the action of TXNRD1 (thioredoxin reductase 1) using NADPH.

NADPH Production: NADPH, essential for antioxidant defense, is produced by various pathways including the PPP (via G6PD), malic enzyme (ME1), and isocitrate dehydrogenase (IDH).

Cystine/Cysteine Cycle:Cystine is imported into the cell via transporters (SLC7A11 and SLC3A2), reduced to cysteine, and used for GSH synthesis. Cysteine can also be oxidized to cystine in the extracellular space, maintaining a redox balance.

Regulatory Proteins and Pathways: SIRT2 deacetylates key metabolic enzymes, affecting their activity.

TRIM36 regulates HK2 stability, affecting glucose metabolism.

ErbB2 and cdc25A influence the activity of PKM2 (pyruvate kinase M2), impacting glycolysis.

Reactive Oxygen Species (ROS) and Oxidative Stress: NADPH oxidases (NOXs) and other enzymes produce ROS such as H2O2 and superoxide (O2•−), which can contribute to oxidative stress.

POR (P450 oxidoreductase) and other pathways further modulate ROS levels and cellular redox state.

Under normal circumstances, GSH(glutathione)-based redox reactions regulate lipid peroxides and their degradation products. However, these lipid peroxides and their degradation products accumulate when GPX4 or xCT are disrupted genetically or inhibited pharmacologically. This accumulation triggers ferroptosis through a poorly understood mechanism that involves membrane destabilization, cytoskeletal changes, and altered proteostasis. {ref} COX-2 and ALOX15 are markers of increased lipid peroxidation and ferroptotic cell death. Many of the key anti-ferroptotic pathway components are under the transcriptional control of NRF2.

GSH is used by GPX4 to reduce lipid peroxides to their alcohol form, an important step in preventing ferroptosis. 

Crosstalk between lipid metabolism and ferroptosis

DGATi: Diacylglycerol O-acyltransferase inhibitor.

n-3/n-6 PUFA: Omega-3 and Omega-6 polyunsaturated fatty acids.

SREBP1: Sterol regulatory element-binding protein 1.

SCD1: Stearoyl-CoA desaturase 1.

AMPK: AMP-activated protein kinase.

ALOX15: Arachidonate 15-lipoxygenase.

miR-522: MicroRNA-522.

PE-AA: Phosphatidylethanolamine-arachidonic acid.

LPCAT3: Lysophosphatidylcholine acyltransferase 3.

AA-CoA: Arachidonic acid-CoA.

ACSL4: Acyl-CoA synthetase long-chain family member 4.

MCT1: Monocarboxylate transporter 1.

xCT: Cystine/glutamate transporter.

CAFs: Cancer-associated fibroblasts. Tumors secrete factors that recruit and activate fibroblasts, transforming them into CAFs. CAFs release a variety of growth factors (e.g., TGF-β, VEGF) and cytokines (e.g., IL-6, IL-8) that promote tumor cell proliferation, survival, and angiogenesis.

STAT1: Signal transducer and activator of transcription 1.

IFNγ: Interferon gamma.

TNFα: Tumor necrosis factor alpha.

GPX4: Glutathione peroxidase 4.

p38: p38 mitogen-activated protein kinases (MAPK).

SLAMF6: Signaling lymphocytic activation molecule family member 6.

PD-1: Programmed cell death protein 1.

PD-L1: Programmed death-ligand 1.

MHC I: Major histocompatibility complex class I.

TCR: T-cell receptor.

CD36: Cluster of differentiation 36.

FA: Fatty acids.

TIM-3: T-cell immunoglobulin and mucin-domain containing-3.

AA metabolites: Arachidonic acid metabolites.

HETEs: Hydroxyeicosatetraenoic acids.

PGE2: Prostaglandin E2.

NK cell: Natural killer cell.

TGFβ1: Transforming growth factor beta 1.

TLR2: Toll-like receptor 2.

XCL1: Chemokine (C motif) ligand 1.

CCL5: C-C motif chemokine ligand 5.

ZEB1: Zinc finger E-box-binding homeobox 1.

SLC7A11: Solute carrier family 7 member 11.

SMA: Smooth muscle actin.

SMAD: Mothers against decapentaplegic homolog.

SAPE-OOH: Hydroperoxyoctadecadienoic acid.

Ferroptosis: A form of cell death characterized by the accumulation of lipid peroxides.

TME: Tumor microenvironment. Lactate: By contributing to a reducing environment, lactate helps protect cancer cells from the oxidative stress that would otherwise lead to ferroptosis. Thus, high lactate levels can inhibit ferroptosis, supporting cancer cell survival.

Sections:

(a): Metabolic pathways and inhibitors affecting ferroptosis in cancer cells.

(b): Role of cancer-associated fibroblasts (CAFs) and exosomes in altering the tumor microenvironment.

(c): Interaction between cancer cells and immune cells (activated and dysfunctional cytotoxic T lymphocytes).

(d): Effects of immune suppressive molecules and signaling on natural killer cells and dendritic cells.

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications {review}

The mTOR pathway promotes resistance to ferroptosis through increased GPX4 protein synthesis (Zhang et al., 2021)and increased sterol response element binding protein (SREBP)-mediated lipogenesis.

Ammonia released from glutamine can activate glucose-regulated N-glycosylated SCAP and dissociate from INSIG, leading to the translocation and activation of SREBP1, thereby promoting adipogenesis

and tumor growth.

GPX4-independent ferroptosis—a new strategy in disease’s therapy {ref}

 ferroptosis and cuproptosis crosstalk in mitochondria. 

Autophagy serves as a catalyst for ferroptosis in cancer therapy {ref} However, the role of autophagy in promoting or inhibiting ferroptosis varies in different cancers, possibly due to tumor heterogeneity or internal and external environmental factors influencing cells.

Copper directly binds to the GPX4 protein, resulting in the formation of GPX4 aggregates and subsequent autophagic degradation of GPX4, ultimately inducing ferroptosis

However, copper may act as an inducer or inhibitor of ferroptosis.

Copper Depletion Strongly Enhances Ferroptosis via Mitochondrial Perturbation and Reduction in Antioxidative Mechanisms {study}

• Targeting copper metabolism: a promising strategy for cancer treatment {review}

FSP1  can protect cells from ferroptosis even when GPX4 activity is compromised. FSP1 reduces CoQ10 to its active antioxidant form, protecting against lipid peroxidation. Active CoQ10 reduces PL-OOH to non-toxic forms (PL-OH), inhibiting FER.

Potential Targets Upstream of FSP1

Transcriptional Regulation: NRF2 inhibitors to reduce FSP1 expression.

Mevalonate Pathway: Statins or other inhibitors to decrease CoQ10 levels.

Lipid Metabolism: Targeting ACSL4, SCD1, or related enzymes to alter lipid composition and oxidative stress.

GPX4 Pathway: Inhibitors of GPX4 or glutathione synthesis to impair antioxidant defenses.

PI3K/AKT Pathway: Inhibitors to modulate cell survival and redox responses.

Energy Metabolism: Targeting AMPK to influence cellular stress response

Docosahexaenoic acid DHA can modulate the expression of SCD1 indirectly. For instance, DHA can downregulate SCD1 expression through their effects on cellular signaling pathways, such as the reduction of sterol regulatory element-binding proteins (SREBPs), which are key transcription factors regulating SCD1 expression.