Table 1 Natural products targeting ferroptosis in lung cancer

Solasonine

Alkaloids

Solanum nigrum L.

Calu-1 and A549 cells

In vitro: 10, 15, 20 μM (calu-1); 20, 25, 30 μM (A549)

Causing GSH redox system imbalance and mitochondrial oxidative stress

Causing iron overload and redox imbalance; lipid peroxidation; mitochondrial damage; the destruction of the GSH redox system: decreasing expression of GPX4, SLC7A11, GSH, and Cys; MMP hyperpolarization

[74]

Erianin

Phenols

Dendrobium

H460 and H1299 cells; Balb/c nude mice

In vitro: 12.5, 25, 50, 100 nm;

In vivo: 100 mg/kg

Inducing Ca²⁺/ CaM signal pathway

Promoting cell cycle arrest in G2/M; activating CAM and regulating L-type voltage-dependent Ca²⁺ channels; lipid peroxidation; promoting the production of ROS, MDA, TRF; decreasing expression of GPX4, CHAC2, SLC40A1, SLC7A11, HO-1, GSH

[75]

Diplacone

Flavonoids

Paulownia tomentosa mature fruit

A549 cells

In vitro: 40 μM

Increasing mitochondrial Ca²⁺ Influx and MPTP

Increasing the level of intracellular Ca²⁺, mitochondrial ROS, and mitochondrial Ca²⁺ overload; increasing the opening of the VDAC and MPTP; inducing loss of MMP; lipid peroxidation

[76]

Qingrehuoxue Formula

Formulas

Chinese herbal medicine

male Balb/c nude mice

In vivo: 15 g/kg

Upregulating P53 and GSK-3β and downregulating Nrf2 signal pathways

Increasing the levels of intracellular ROS, Fe²⁺, H₂O_2, GSH and MDA↑; decreasing the expression of SLC7A11, GPX4; shrunking mitochondria with increasing membrane density and decreasing or disappearing mitochondrial cristae

[78]

Bufotalin

Steroids

Venenum bufonis

A549 cells; male Balb/c nude mice

In vitro: 4 μM;

In vivo: 5/10 mg/kg

Facilitating the ubiquitination and degradation of GPX4

Increasing the level of lipid ROS, 4-HNE, MDA, Fe2 + ; decreasing the ratio of GSH/GSSG and NADPH/NADP + 

[32]

Dihydroisotans-hinone I

Quinones

Salvia miltiorrhiza Bunge

A549, H460 and IMR-90 cells; xenograft nude mice

In vitro: 20–30 μM;

In vivo: 30 mg/kg

Blocking the protein expression of GPX4

Increasing the level of lipid ROS and MDA; decreasing expression of GPX4 and GSH

[80]

Sanguinarine

Alkaloids

Sanguinaria canadensis Linn

A549 and H3122 cells; xenograft mice

In vitro: 10 μM;

In vivo: 5 mg/kg

Decreasing the protein stability of GPX4 through E3 ligase STUB1-mediated ubiquitination and degradation of GPX4

Increasing Fe²⁺ concentration, ROS level, and MDA content; decreasing GSH content

[81]

Red ginseng polysaccharide

Polysaccharides

Panax ginseng

A549 and MDA-MB-231 cells

In vitro: 200 μg/ml

Blocking the protein expression of GPX4

Increasing the release of LDH and the level of lipid ROS; decreasing expression of GPX4

[82]

Timosaponin AIII

Steroids

Anemarrhena Asphodeloides Bunge

H1299, A549, SPC-A1 and LLC cells; male C57BL/6 J or Balb/c- nude mice

In vitro: 4 μM;

In vivo: 12.5 mg/kg (low-dose), 50 mg/kg (high-dose)

Facilitating HSP90 mediated GPX4 ubiquitination and degradation

Suppressing cell proliferation and migration, inducing G2/M phase arrest; increasing the levels of iron, lipid ROS, MDA, HMOX-1; decreasing expression of GSH, FTL, GPX4, SLC40A1, SLC7A11; inducing loss of MMP

[83]

Zerumbone

Terpenoids

Zingiber zerumbet rhizomes

HPAEpiC, A549, and H460 cell; BALB/c nude mice

In vitro: 100 μM;

In vivo: 20 mg/kg (low-dose), 40 mg/kg (high-dose)

Downregulating AKT/STAT3/SLC7A11 axis

Increasing the level of MDA; decreasing the levels of GSH, GPX4 and SLC7A11

[86]

S-3′-hydroxy-7′, 2′, 4′-Trimethoxyisoxane

Flavonoids

Dalbergia odorifera T. Chen

A549 and H460 cells; Balb/c nude mice

In vitro: 16 μM;

In vivo: –

Inhibiting Nrf2/HO-1 signaling pathway

Increasing the level of Fe2 + , ROS and MDA; decreasing the levels of GSH, GPX4, p21, FTH1, Nrf2, HO-1; TEM: cell membrane rupture, mitochondrial shrinkage, thickening of the mitochondrial membrane density, and diminished or disappeared mitochondrial ridges

[88]

Ginkgetin

Flavonoids

Ginkgo biloba leaves

Xenograft nude mice

In vitro: 5 μM;

In vivo: 30 mg/kg

Inhibiting Nrf2/HO-1 signaling pathway

Increasing labile iron pool and lipid peroxidation; decreasing expression of SLC7A11, GPX4, GSH; inducing loss of MMP

[89]

Manoalide

Terpenoids

Sponges

A549, H157, HCC827, and PC9 cells

In vitro: 15 μM

Suppressing the KRAS-ERK pathway and the Nrf2-SLC7A11 axis, mitochondrial Ca2 + overload induced-FTH1 pathways

Inducing ER stress; promoting the accumulation of lipid droplets, ROS, lipid peroxidation, mitochondria Ca2 + and iron; increasing the oxygen consumption rate and inhibiting mitochondria fatty acid oxidation; decreasing expression of Nrf2, SLC7A11, FTH1, GPX4, KRAS, P-ERK/ERK; increasing expression of NCOA4 and P-AMPK/AMPK

[90]

Hedyotisdiffusa injection

Other

Chinese herbal medicine

A549 and H1975 cells; Balb/c nude mice xenograft model

In vitro: 30 μM (A549), 40 μM (H1975);

In vivo: 15 mg/kg

Regulating Bax/Bcl2/VDAC2/3 axis

Regulating VDAC2/3 activity by promoting Bax via inhibiting Bcl2; increasing the expression of 4-HNE, TFR, and HMOX1

[91]

D-Borneol

Terpenoids

Cinnamomum cam phora (L.) J. Presl

H460/CDDP cells; Xenograft tumor mice

In vitro: 2 μg/ml;

In vivo: 30 mg/kg (low-dose), 60 mg/kg (high-dose)

Promoting NCOA4-mediated ferritinophagy

Increasing the level of ROS, MDA; decreasing expression of GSH, SOD, Trx, HO-1

[92]

Artesunate

Terpenoids

Artemisinin

NCI-H1299, A549, LTEP-a-2, NCI-H23, and NCI-H358 cells

In vitro: 10/30 μM

Inhibiting system Xc − 

and activating TFRC

Increasing the ROS level and the mRNA level of TFRC; decreasing the protein level of VDAC and SLC7A11;

[93]

Dihydroartemisinin

Terpenoids

Artemisinin

NCI-H1299, A549, LTEP-a-2, NCI-H23, and NCI-H358 cells

In vitro: 10/30 μM

Inhibiting system xc − 

and activating TFRC

Increasing the ROS level and the mRNA level of TFRC; decreasing the protein level of VDAC and SLC7A11;

[93]

Curcumenol

Terpenoids

Wenyujin

CCD19, H1299, H460, BEAS-2B and 293 T cells

In vitro: 300 μg/ml;

In vivo: 200 mg/kg

Suppressing lncRNA H19/miR-19b-3p/FTH1 axis

Increasing the level of iron, lipid ROS, HO-1, MDA, TF; decreasing the level of GSH, Nrf2, GPX4, SLC7A11, SLC40A1, FTH1

[96]

Sulforaphane

Glycosides

Cruciferous vegetables

NCI-H69, NCI-H82 and NCI-H69AR cells

In vitro: 20 μM

Inhibiting system Xc − 

Decreasing the level of SLC7A11, GSH; increasing the level of Fe2 + , lipid peroxidation

[97]

Sinapine

Alkaloids

Rapeseed and cruciferous plant species

A549, SK, H66, H460 and HBE cells

In vitro: 20 μM

Upregulating p-53,TF, TFRC; downregulating SLC7A11

Increasing intracellular ferrous iron, lipid peroxidation, MDA and ROS; decreasing the expression of SLC7A11, GSH, GPX4

[101]

HO-3867

Other

Curcumin analogs

H460, PC-9, H1975, A549, H1299, A549 p53 KO cells and H460 p53 KO cells

In vitro: 40 μM

Activating the p53-DMT1 axis and suppressing GPX4

Increasing the level of iron, ROS; increasing expression of P53, DMT1; decreasing expression of SLC7A11, GPX4

[102]

6-Gingerol

Phenols

Ginger

A549 and CCD19-Lu cells; Balb/c nude mice

In vitro: 20, 40, 80 μM;

In vivo: 0.25 mg/kg (low-dose), 0.5 mg/kg (high-dose)

Inhibiting USP14-mediated Beclin1 ubiquitination, enhancing autophagy-dependent ferroptosis

Increasing level of MDA, iron and TfR1; decreasing level of USP14, FTH1, GPX4, ATF4, SOD; increasing autophagy related proteins level of Beclin- 1, NCOA4, LC3 I, LC3 II

[103]

Realgar

Other

Sulfide minerals

H23 cells

In vitro: 2 μg/ml

Suppressing the KRAS/Raf/MAPK pathway

Increasing the level of MDA, Fe2 + , ROS; decreasing expression of GSH; inducing loss of MMP

[106]

Curcumin

Phenols

Turmeric plant

A549 and H1299 cells; female C57BL/6 mice

In vitro: 30 μM;

In vivo: 100 mg/kg

Activating autophagy-dependent ferroptosis

Increasing the level of iron, lipid peroxidation, ROS, MDA, IREB2, ACSL4; decreasing the level of SOD, GSH, SLC7A11, GPX4; inducing mitochondrial membrane rupture; decreasing mitochondrial cristae; increasing autolysosome; increasing autophagy related proteins level of Beclin1 and LC3, and decreasing the level of P62

[108]

Resveratrol

Phenols

Peanuts, grapes, knotweed, mulberries

H520 cells

In vitro: 50 μmol/L;

Regulating SLC7A11-HMMR interaction, enhancing the cytotoxic effect of CD8 + T cells

Increasing the level of MDA, ACSL4, TFRC; decreasing the level of GPX4, SLC7A11, HMMR, GSH, and SOD; promoting the release of TNF-α, IFN-γ, IL-12, and IL-2; enhancing the cytotoxic effects of CD8 + T cells

[111]

Resveratrol

Phenols

Peanuts, grapes, knotweed, mulberries

BEAS-2B cells

In vitro: 10 μM;

Activating the Nrf2/Keap1 signaling pathway

Decreasing reactive oxygen species production and iron deposition; increasing the expression of GPX4 and GSH

[112]