Table 2 Natural products targeting ferroptosis in ALI

Astaxanthin

Terpenoids

Various microorganisms, phytoplankton, marine animals, and seafood

In vitro: LPS induced RAW264.7 cells;

In vivo: LPS induced female Balb/c mice

In vitro: 5, 10, 20 μM;

In vivo: 20 mg/kg

Activating the Keap1-Nrf2/HO-1 pathway

Decreasing inflammatory relative: COX2, iNOS, NO↓; NF-KB, P-P65↓; decreasing lipid metabolism relative: lipid ROS↓; inhibiting ferroptosis relative: 4-HNE, PTGS2, ACSL4 and CD68↓; SLC7A11, GPX4 and FTH1↑

[121]

Panaxydol

Polyacetylenes

Panax ginseng

In vitro: LPS induced BEAS-2B cells;

In vivo: LPS induced male C57BL/6 mice

In vitro: 40 μg/ml;

In vivo: 20 mg/kg

Activating the Keap1-Nrf2/HO-1 pathway

Decreasing inflammatory relative: TNF-α, IL-1β, and IL-6↓; MPO activity, neutrophil percentage (%) ↓; reducing pulmonary edema: Lung W/D ratio, total protein↓; inhibiting ferroptosis relative: Fe2 + , MDA ↓; GSH and GPX4 ↑

[30]

Urolithin A

Phenols

A secondary metabolite of ellagitannins and ellagic acid

In vitro: LPS induced BEAS-2B cells;

In vivo: LPS induced male C57BL/6 mice

In vitro: 10 μM;

In vivo: 50 mg/kg

Activating the Keap1-Nrf2/HO-1 pathway

Decreasing inflammatory relative: TNF-α, IL-1β, and IL-6↓; neutrophil percentage (%) ↓; reducing pulmonary edema; Lung W/D ratio, total protein↓; reducing oxidative stress: Intracellular ROS and mitochondrial ROS, MDA↓; GSH, CAT, SOD↑; inhibiting ferroptosis relative: GPX4, SLC7A11↑; Fe2 + , 4-HNE↓; the number of mitochondria↑, mitochondria structural damage↓

[128]

Obacunone

Flavonoids

Citrus and rutaceae species

In vitro: LPS induced BEAS-2B cells;

In vivo: LPS induced male C57BL/6 mice

In vitro: 20 μM;

In vivo: 2.5, 5, 10 mg/kg

Activating the Nrf2/SLC7A11/GPX4 axis

Decreasing inflammatory relative: IL-1β, IL-6, TNF-α↓; KL-6, CRP and neutrophils (%) ↓; lymphocytes (%) ↑; reduced the LPS-induced loss of ALI lung tissue structure loss, apoptosis injury, and edema; reducing oxidative stress: CAT, GSH, SOD↑; MDA↓; inhibiting ferroptosis relative: Fe 2 + , 4-HNE↓; GPX4, SLC7A11↑; TEM: mitochondrial structural damage

[131]

Wedelolactone

Lactones

Eclipta prostrata

In vitro: LPS induced AR42J cells;

In vivo: sodium taurocholate or caerulein induced male Sprague–Dawley rats

In vitro: 20 μM;

In vivo: 20, 50 mg/kg (taurocholate-induced), 50, 100 mg/kg (caerulein-induced)

Activating GPX4 level

Decreasing proinflammatory cytokines: TNF-α, IL-1β, IL-18, NLRP3↓; reducing oxidative stress: ROS, MDA↓; inhibiting lipid peroxidation and ferroptosis: GSH, GSH-Px, GPX4, GSDMD, DGSDMD-N↑, 4-HNE↓; decreasing serum pancreatic digestive enzymes: LDH, amylase, lipase↓; inhibiting pyroptosis: caspase1, caspase11↓

[133]

Qingyi Decoction

Formulas

Chinese herbal medicine

In vivo: Sodium taurocholate induced Aprague-Dawley male rats

In vivo: 10 g/kg

Activating ALDH2/ANXA1; downregulating ICAM-1

Decreasing inflammatory relative: TNF-α and IL-6↓; inhibiting the increase of serum amylase and Lung W/D ratio; reducing neutrophil infiltration: ANXA1↑, ICAM-1, P-P65/P65↓; inhibiting ferroptosis relative: Fe2 + , MDA, MPO↓; ALDH2, GSH, SLC7A11, FTH1 and GPX4↑

[134]

Matrine

Alkaloids

Sophora flavescens

In vitro: LPS-induced BEAS-2B cells and MLE-12 cells;

In vivo: cerulein and LPS induced UCP2 -/- mice

In vitro: -;

In vivo: 200 mg/kg

Activating the UCP2/SIRT3/PGC1αpathway

Decreasing inflammatory cytokines: IL-6, IL-1β, and TNF-α, total BALF protein↓; reducing lipid peroxidation: intracellular ROS, MPO↓; inhibiting ferroptosis: Fe2 + , MDA, ACSL4↓; GSH, GPX4, NRF1, mtTFA, HO-1 and NQO1↑

[136]

Sipeimine

Alkaloids

Fritillaria roylei

In vivo: PM2.5 dust suspension induced male Sprague–Dawley rats

In vivo: 15 mg/kg (low-dose), 30 mg/kg (high-dose)

Activating the PI3K/Akt/Nrf2 pathway

Decreasing inflammatory cytokines: TNF-α and IL-1β↓; inhibiting ferroptosis relative: MDA, 4-HNE, iron↓; Nrf2, GSH, GPX4, HO-1, SLC7A11 and FTH1↑; the mitochondria ultrastructure was significantly improved

[140]

Tectoridin

Flavonoids

The rhizome of Belamcanda chinensis

In vitro: PM2.5-induced BEAS-2B cell;

In vivo: PM2.5-induced Nrf2-knockout mice

In vitro: 100 μM;

In vivo: 50 mg/kg (low-dose), 100 mg/kg (high-dose)

Activating the Nrf2/SLC7A11/GPX4 axis

Decreasing inflammatory factors, lipid peroxidation, iron accumulation and ferroptosis: MDA↓, GSH, GPX4, xCT, FTH1/FTL, TFR↑

[141]

Rosavin

Glycosides

Rhodiola plants

In vivo: PM2.5 dust suspension induced male Sprague–Dawley rats

In vivo: 50 mg/kg (low-dose), 100 mg/kg (high-dose)

Activating the PI3K/Akt/Nrf2 pathway

inhibiting ferroptosis relative: MDA, 4-HNE, iron↓; Nrf2, GSH, GPX4↑

[142]

Astragaloside IV

Glycosides

Astragalus

In vivo: PM2.5 dust suspension induced C57BL/6 J male mice

In vivo: 50 mg/kg (low-dose), 100 mg/kg (high-dose)

Activating the Nrf2/SLC7A11/GPX4 axis

Reducing pulmonary edema; reducing oxidative stress: MDA and MPO↓; SOD↑; decreasing inflammatory cytokines: IL-6, TNF-α, IL-1β and COX2↓; inhibiting ferroptosis relative: Nrf2, HO-1, SLC7A11, GPX4, FLC, FTH1↑; TFRC↓; the mitochondria ultrastructure was significantly improved

[143]

Isoliquiritin apioside

Flavonoids

Glycyrrhizae radix et rhizoma

In vitro: Hypoxia and reoxygenation induced MLE-2 cells;

In vivo: I/R induced male C57BL/6 mice

In vitro: 25, 50, 100 μM;

In vivo: 50 mg/kg (low-dose), 100 mg/kg (high-dose)

Inhibiting Hif-1α/HO-1 pathway

Decreasing proinflammatory cytokines: TNF-α, IL-6, Hmgb1↓; inhibiting ferroptosis: MDA, Fe2 + , Ptgs2, ACSL4↓; GSH, GPX4↑

[148]

Salidroside

Glycosides

Rhodiola rosea

In vivo: Hyperoxia-induced KM mice

In vivo: 100 mg/kg

Inhibiting the Act1/TRAF6/p38 MAPK pathway

Decreasing inflammatory and immunity relative: IL-6, TGF-β, IL-17A, IL-17RA↓; inhibiting ferroptosis relative: Fe 2 + , MDA↓; GPX4↑; reducing pulmonary edema, atelectasis, necrosis, alveolar and interstitial inflammation, and collagen deposits

[151]

Ferulic acid

Phenols

In various kinds of plants and vegetables such as tomatoes, sweet corn and rice bran

In vitro: LPS induced MLE-12 cells;

In vivo: female Balb/c mice were induced by the CLP

In vitro: 0.1 μM;

In vivo: 100 mg/kg

Activating the Nrf2/HO-1 pathway

Ameliorating barrier dysfunction and pulmonary edema: Lung W/D ratio, total protein↓; ZO-1, occludin, and claudin-1, TEER↑; FITC-dextran flux↓; inhibiting ferroptosis relative: ROS, MPO, Fe2 + , MDA↓; GSH, GPX4↑

[156]

Puerarin

Flavonoids

Gegen

In vitro: LPS induced A549 cells

In vitro: 80 μM

Activating SLC7A11/ GPX4 axis and FTH1

Decreasing inflammatory relative: TNF-α, IL-8, and IL-1β↓; decreasing lipid peroxidation: MDA, ROS↓; inhibiting ferroptosis relative: total iron levels and ferrous iron, NOX1↓; SLC7A11, GPX4, GSH, FTH1↑

[157]

Tripterygium wilfordii Hook.f

Terpenoids

Celastraceae plants

In vivo: Male Balb/c mice were induced by PQ

In vivo: 10 g/kg

Modulating the Keap1/Nrf2/HO-1 pathway

Reducing the levels of proinflammatory cytokines:

IL-6 and TNF-α; alleviating oxidative stress: MDA↓; GSH, SOD↑

[161]

Proanthocyanidins

Flavonoids

Carthamus tinctorius L

In vivo: Mice were infected by IAV and HINI

In vivo: 20 mg/kg

Inhibiting the TGF-β1/Smad signaling pathway and IFN-γ expression

Decreasing the levels of MDA and ACSL4; upregulating the expression of GSH, GPX4, and SLC7A11;

[162]

Naringenin

Flavonoids

Citrus fruits

In vitro: AgNPs induced BEAS-2B cells;

In vivo: AgNPs suspension induced male ICR mice

In vitro: 25, 50, 100 μM;

In vivo: 25, 50, 100 mg/kg

Activating the Nrf2/HO-1 pathway

anti-inflammation, anti-oxidative stress, anti-apoptosis: BAX, CytC, Caspase9, Caspase3↓; Bcl2↑; anti-ferroptosis; decreasing the levels of white blood cells, neutrophils, and lymphocytes in the blood, ameliorating lung injury, suppressing the release of pro-inflammatory cytokines;

[164]