Table 2.
Natural products targeting ferroptosis in ALI
| Component | Classification | Main roots | Test models | Dose | Mechanisms | Specific effects | Refs. |
|---|---|---|---|---|---|---|---|
| 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] |
↑: up-regulation, increase or activation; ↓: down-regulation, decrease or inhibition