Ferroptosis and Its Potential Role in Lung Cancer: Updated Evidence from Pathogenesis to Therapy

Figures & data

Table 1 Cell Morphology, Biochemical Features, and Key Regulators of Necrosis, Autophagy, Apoptosis, Pyroptosis, Ferroptosis

Type of Cell Death	Identification	Cell Morphology	Biochemical Features
Necrosis	Traumatic cell death due to mechanical shear stress or other physicochemical factors.	Mitochondria swells in cytoplasm, forming vesicles of different sizes, and mitochondrial cristae break until they disappear. Cytoplasm can lose water, and cell volume is reduced.	Necrosome
Autophagy	A process of engulfing one’s own cytoplasmic proteins or organelles and coating them into vesicles, fusing with lysosomes to form autophagic lysosomes, and degrading the contents it encapsulates.	Autolysosome accumulation, cytoplasmic vacuolization.	Conversion from light chain 3 (LC3)-I to LC3-II, degradation of p62Lck, Beclin-1 dissociation from Bcl-2/XL
Apoptosis	A morphologically distinct form of programmed cell death that is mediated by a number of proteases that cleave their target proteins at specific aspartate residues.	Plasma membrane blebbing; reduction of cellular and nuclear volume; nuclear fragmentation; and chromatin condensation	Activation of caspases and proapoptotic Bcl-2 family proteins, oligonucleosomal DNA fragmentation, exposure of Plasma membrane rupture, dissipation of dissipation.
Pyroptosis	A unique form of programmed cell death mediated by the gasdermin family of proteins and causes lytic cell death and release of proinflammatory cytokines.	Cellular swelling and lysis, release inflammatory factors.	Inflammasome
Ferroptosis	A type of regulated cell death caused by an excess iron-dependent accumulation of lipid peroxides and is morphologically and biochemically distinct from other types of cell death.	Small mitochondria with a condensed mitochondrial membrane, vanishing or reduction of mitochondria crista, and rupture of outer mitochondrial membrane	Iron loading, ROS accumulation, System Xc− inhibition with reduced GSH, GPX4 inhibition

Figure 1 Main regulatory mechanism of ferroptosis. Iron homeostasis, and lipid peroxidation metabolism are core regulators of ferroptosis.

Abbreviations: TFR1, transferrin receptor 1; DMT1, divalent metal ion transporter 1; FPN, ferroportin; IRP, iron regulatory protein; PHD1, prolyl hydroxylase domain protein 1; HSPB1, heat shock protein β-1; FIN56, specific iron death inducer; System Xc-, cystine/glutamate transporter; Cys, cysteine; Glu, glutamic; Gln, glutamine; GLS, glutaminase; GSH, glutathione; GPX4, glutathione peroxidase 4; Hcy, homocysteine; CGL, cystathionine-γ-lyase; HOX1, heme oxygenase-1; PRDX6, peroxide reduction enzyme-6; CISD1, CDGSH iron sulfur domain 1.

Table 2 Nanoparticle Inducers in Ferroptosis for Lung Cancer

Nanoparticle Inducers	Mechanism	Model	Advantages	Reference
FeCO-DOX@MCN	Iron loading, ROS level increase, GSH depletion, GPX4 inactivation	In-vitro: MCF-7, A549, HeLa; In-vivo: MCF-7	Under the guidance of photoacoustic imaging, the FeCO-DOX@MCN nanoplatform demonstrates high treatment efficacies in vitro and in vivo by combination of chemotherapy, photothermal therapy and gas therapy.	[^Citation88]
Exosome-like nanovesicles (eNVs-FAP)	eNVs-FAP vaccine-activated cellular immune responses could promote tumor ferroptosis by releasing interferon-gamma (IFN-γ) from CTLs and depleting FAP+CAFs.	Colon, melanoma, lung, and breast cancer models	eNVs-FAP showed excellent antitumor effects in a variety of tumor-bearing mouse models.	[^Citation89]
Phenylboronate ester (PBE)	The nanoparticles can perform acid-activatable photodynamic therapy by protonation of the ionizable core, and significantly recruit tumor-infiltrating T lymphocytes for interferon gamma secretion, and thus sensitize the tumor cells to RSL-3-inducible ferroptosis.	Lung metastasis of 4T1 breast tumors	The combination of nanoparticle-induced ferroptosis and blockade of programmed death ligand 1 efficiently inhibits growth of B16-F10 melanoma tumor and lung metastasis of 4T1 breast tumors, suggesting the promising potential of ferroptosis induction for promoting cancer immunotherapy.	[^Citation90]
Zero-valent-iron nanoparticle (ZVI-NP)	ZVI-NP caused mitochondria dysfunction, intracellular oxidative stress, and lipid peroxidation, leading to ferroptotic death of lung cancer cells. Degradation of NRF2 by GSK3/β-TrCP through AMPK/mTOR activation was enhanced in such cancer-specific ferroptosis.	Immunocompetent mice and humanized mice.	This dual-functional nanomedicine established an effective strategy to synergistically induce ferroptotic cancer cell death and reprogram the immunosuppressive microenvironment, which highlights the potential of ZVI-NP as an advanced integrated anti-cancer strategy.	[^Citation91]
Citric acid iron oxide nanoparticles (IONPs-Ac)	It displayed important cytotoxicity in a human lung cancer cells model (A549 cells), even at low concentrations, whereas free IONPs-Ac displayed adequate biocompatibility.	A549 cells	It was possible to infer that ferri-liposomes were able to induce A549 tumor cells death through apoptosis/ferroptosis processes, evidenced by a significant reduction of the mitochondrial membrane potential.	[^Citation92]
Erastin/MT1DP@FA-LPs (E/M@FA-LPs)	Folate (FA)-modified liposome (FA-LP) nanoparticles for targeted co-delivery of erastin and MT1DP to enhance the bioavailability and the efficiency of the drug/gene combination.	A549 and H1299 cells	Identify a novel strategy to elevate erastin-induced ferroptosis in NSCLCs acting through the MT1DP/miR-365a-3p/NRF2 axis.	[^Citation93]

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