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Ferroptosis in e-cigarette aerosol-associated respiratory injury

Sailis AB

Arch Toxicol, 2026 Nov;100(11):5247-5260.
PMID: 42362750 DOI: 10.1007/s00204-026-04486-w

E-cigarette use has increased substantially, particularly among adolescents and young adults, yet its long-term respiratory effects remain incompletely understood. E-cigarette aerosol contains biologically active constituents, including nicotine, propylene glycol, vegetable glycerin, flavoring chemicals, aldehydes, metals, particles, and reactive oxygen species, which may disrupt respiratory epithelial homeostasis. This review synthesizes experimental, preclinical, and human-relevant evidence linking e-cigarette aerosol exposure to respiratory epithelial injury, with emphasis on ferroptosis-related mechanisms. Available evidence indicates that e-cigarette aerosol can impair epithelial barrier integrity, alter mucociliary defense, increase MUC5AC expression, induce oxidative stress, and promote inflammatory signaling. Emerging preclinical data suggest that electronic nicotine delivery system exposure may induce ferroptosis-associated lung injury through increased CD71/TFR1 and ACSL4 expression, reduced GPX4, altered lipid profiles, BODIPY-C11-positive lipid peroxidation, epithelial cell death, inflammation, mucus accumulation, emphysema-like pathology, and fibrosis. Mechanistically, e-cigarette aerosol may create a ferroptosis-permissive epithelial environment by promoting redox imbalance, GPX4/GSH/SLC7A11 antioxidant defense impairment, altered iron handling, ACSL4-mediated PUFA-phospholipid remodeling, NRF2/ARE stress responses, mitochondrial dysfunction, and lipid peroxide accumulation. Ferroptotic epithelial injury may further amplify airway inflammation and remodeling through DAMP release, macrophage recruitment, cytokine production, barrier disruption, mucus dysregulation, and extracellular matrix deposition. However, direct human evidence remains limited, and many mechanistic links are extrapolated from cigarette smoke, particulate matter, and broader lung injury models. Future studies should use standardized exposure systems, human-relevant airway and alveolar models, comprehensive ferroptosis markers, and ferroptosis-specific rescue experiments to determine whether ferroptosis is a driver, amplifier, or downstream marker of e-cigarette-associated respiratory injury.

Matched MeSH terms: Respiratory Mucosa/drug effects
Acanthamoebicidal activity of periglaucine A and betulinic acid from Pericampylus glaucus (Lam.) Merr. in vitro

Mahboob T, Azlan AM, Shipton FN, Boonroumkaew P, Nor Azman NS, Sekaran SD, et al.

Exp Parasitol, 2017 Dec;183:160-166.
PMID: 28916456 DOI: 10.1016/j.exppara.2017.09.002

Acanthamoeba species are pathogenic protozoa which account for amoebic keratitis, conjunctivitis and granulomatous amoebic encephalitis. These amoebae form cysts which resist drugs and more effective acanthamoebicidal agents are needed. Medicinal plants could be useful in improving the current treatment strategies for Acanthamoeba infections. In the present study, we examined the amoebicidal effects of Pericampylus glaucus (Lam.) Merr., a medicinal plant used for the treatment of conjunctivitis in Malaysia. Pathogenic Acanthamoeba triangularis were isolated from environmental water samples and treated with different concentrations of fractions obtained from Pericampylus glaucus (Lam.) Merr. as well as main constituents for 24-72 h. Chlorhexidine was used as a reference drug. Ethanol fraction of stem showed significant (p

Matched MeSH terms: Respiratory Mucosa/drug effects
Fulltext Bile acids at neutral and acidic pH induce apoptosis and gene cleavages in nasopharyngeal epithelial cells: implications in chromosome rearrangement

Tan SN, Sim SP

BMC Cancer, 2018 04 12;18(1):409.
PMID: 29649994 DOI: 10.1186/s12885-018-4327-4

BACKGROUND: Chronic rhinosinusitis (CRS) increases the risk of developing nasopharyngeal carcinoma (NPC) while nasopharyngeal reflux is known to be one of the major aetiological factors of CRS. Bile acid (BA), the component of gastric duodenal contents, has been recognised as a carcinogen. BA-induced apoptosis was suggested to be involved in human malignancies. Cells have the potential and tendency to survive apoptosis. However, cells that evade apoptosis upon erroneous DNA repair may carry chromosome rearrangements. Apoptotic nuclease, caspase-activated deoxyribonuclease (CAD) has been implicated in mediating translocation in leukaemia. We hypothesised that BA-induced apoptosis may cause chromosome breaks mediated by CAD leading to chromosome rearrangement in NPC. This study targeted the AF9 gene located at 9p22 because 9p22 is one of the most common deletion sites in NPC.
METHODS: We tested the ability of BA at neutral and acidic pH in inducing phosphatidylserine (PS) externalisation, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) disruption, and caspase 3/7 activity in normal nasopharyngeal epithelial (NP69) and NPC (TWO4) cells. Inverse-PCR (IPCR) was employed to detect AF9 gene cleavages. To investigate the role of CAD in mediating these cleavages, caspase inhibition was performed. IPCR bands representing AF9 cleaved fragments were sequenced.
RESULTS: BA-treated cells showed higher levels of PS externalisation, ROS production, MMP loss and caspase 3/7 activity than untreated control cells. The effect of BA in the induction of these intracellular events was enhanced by acid. BA at neutral and acidic pH also induced significant cleavage of the AF9 gene. These BA-induced gene cleavages were inhibited by Z-DEVD-FMK, a caspase-3 inhibitor. Intriguingly, a few chromosome breaks were identified within the AF9 region that was previously reported to participate in reciprocal translocation between the mixed lineage leukaemia (MLL) and AF9 genes in an acute lymphoblastic leukaemia (ALL) patient.
CONCLUSIONS: These findings suggest a role for BA-induced apoptosis in mediating chromosome rearrangements in NPC. In addition, CAD may be a key player in chromosome cleavages mediated by BA-induced apoptosis. Persistent exposure of sinonasal tract to gastric duodenal refluxate may increase genomic instability in surviving cells.

Matched MeSH terms: Respiratory Mucosa/drug effects
Fulltext The phosphorylation of endogenous Nedd4-2 In Na(+)-absorbing human airway epithelial cells

Ismail NA, Baines DL, Wilson SM

Eur J Pharmacol, 2014 Jun 05;732:32-42.
PMID: 24657276 DOI: 10.1016/j.ejphar.2014.03.005

Neural precursor cell expressed, developmentally down-regulated protein 4-2 (Nedd4-2) mediates the internalisation / degradation of epithelial Na(+) channel subunits (α-, β- and γ-ENaC). Serum / glucocorticoid inducible kinase 1 (SGK1) and protein kinase A (PKA) both appear to inhibit this process by phosphorylating Nedd4-2-Ser(221), -Ser(327) and -Thr(246). This Nedd4-2 inactivation process is thought to be central to the hormonal control of Na(+) absorption. The present study of H441 human airway epithelial cells therefore explores the effects of SGK1 and / or PKA upon the phosphorylation / abundance of endogenous Nedd4-2; the surface expression of ENaC subunits, and electrogenic Na(+) transport. Effects on Nedd4-2 phosphorylation/abundance and the surface expression of ENaC were monitored by western analysis, whilst Na(+) absorption was quantified electrometrically. Acutely (20min) activating PKA in glucocorticoid-deprived (24h) cells increased the abundance of Ser(221)-phosphorylated, Ser(327)-phosphorylated and total Nedd4-2 without altering the abundance of Thr(246)-phosphorylated Nedd4-2. Activating PKA under these conditions did not cause a co-ordinated increase in the surface abundance of α-, β- and γ-ENaC and had only a very small effect upon electrogenic Na(+) absorption. Activating PKA (20min) in glucocorticoid-treated (0.2µM dexamethasone, 24h) cells, on the other hand, increased the abundance of Ser(221)-, Ser(327)- and Thr(246)-phosphorylated and total Nedd4-2; increased the surface abundance of α-, β- and γ-ENaC and evoked a clear stimulation of Na(+) transport. Chronic glucocorticoid stimulation therefore appears to allow cAMP-dependent control of Na(+) absorption by facilitating the effects of PKA upon the Nedd4-2 and ENaC subunits.

Matched MeSH terms: Respiratory Mucosa/drug effects