Numerous studies have highlighted the role of ferroptosis in both the etiology and treatment of various forms of cancer, including but not limited to aggressive types such as breast cancer, liver cancer, stomach cancer, rectal cancer, glioma, and pancreatic cancer [69]. Targeting ferroptosis in the context of lung cancer has the potential to mitigate disease progression and metastasis, as well as to overcome, to some extent, the drug and radiation resistance commonly exhibited by lung cancer cells. Non-small cell lung cancer (NSCLC) constitutes the predominant subtype of lung cancer, accounting for approximately 85% of cases and encompassing squamous cell carcinoma, large cell carcinoma, and adenocarcinoma [70, 71]. Consequently, contemporary research on ferroptosis in lung cancer is primarily focused on NSCLC. Chemotherapy remains the principal treatment modality in the clinical management of NSCLC, with cisplatin being the most frequently employed chemotherapeutic agent [72]. However, the emergence of cisplatin resistance poses a significant challenge to achieving optimal therapeutic outcomes in patients undergoing chemotherapy for lung cancer. Natural products have gained prominence as a valuable adjunct in the comprehensive treatment of various malignancies. Besides, natural products have been shown to positively impact the quality of life and extend the survival duration of patients with advanced lung cancer, irrespective of whether conventional treatments are administered [73]. A summary of natural products used in lung cancer therapy, their primary sources, mechanisms of targeting ferroptosis, and main effects can be found in Table 1. Additionally, we analyzed and summarized the targets and signaling pathways of natural products targeting ferroptosis in the treatment of lung diseases, as shown in Figs. 1, 2.

The role of SLC7A11-GSH-GPX4 axis in natural products—modulated ferroptosis in respiratory diseases. The modulations of ferroptosis by natural products in respiratory diseases are orchestrated through various mechanisms, prominently via GPX4-related pathways. These pathways crucially influence lipid peroxidation, an essential process in ferroptosis. Natural products up-regulate Nrf2 gene expression, stimulating its downstream target HO-1 and enhancing SLC7A11 protein expression. Consequently, GPX4 is activated either directly or indirectly, inhibiting ferroptosis. Moreover, multiple targets are involved in regulating the SLC7A11/GPX4 axis, including the activation of system Xc− , which facilitates GSH synthesis and GPX4 activation to modulate ferroptosis. On the contrary, ACSL4 overexpression catalyzes the oxidation of PUFAs into lipid hydroperoxides. These hydroperoxides are then converted into non-toxic lipid alcohols through GPX4 activation. In the context of the immune response, Interleukin IL-17 hinders GPX4, leading to induced ferroptosis. Notations: Black Arrow (↓): Indicates promotion. Red Rough Arrow (⟂): Indicates inhibition. Green Arrow: Indicates a decrease. Red Arrow: Indicates a increase.

The role of iron metabolism in natural products—modulated ferroptosis in respiratory diseases. Iron metabolism is intimately linked with the mechanisms through which TCM modulates ferroptosis in respiratory diseases. An accumulation of a significant amounts of ferrous ions initiates the Fenton reaction, thereby enhancing lipid peroxidation, a pivotal step in inducing ferroptosis. Free iron binds with ferritin and is subsequently transported to the endosome through the transferrin receptor. Within the endosome, STEAP3 catalyzes the conversion of ferric iron into ferrous iron, which is then channeled into the labile iron pool via DMT1. The oxidation of PUFA coincides with the formation of ferrous ions. The influx of calcium ions causes mitochondrial calcium overload, leading to a substantial accumulation of ROS, the destruction of FLC, and FTH. These events culminate in the release of ferrous ions from the labile iron pools and the Fenton reaction, precipitating ferroptosis. Moreover, factors such as Nrf2, Hif-1α, HO-1, and mtTFA accentuate the increase of labile iron, while ferritophagy emerges as another pathway inducing ferroptosis. Notations: Black Arrows (↓): Indicate facilitation. Red Rough Arrows (⟂): Indicate inhibition. Green Arrows: Indicate a decrease

Solasonine (SS), a glycoalkaloid from Solanum nigrum L, demonstrates potential in cancer therapy, showing antitumor effects on lung cancer cells. Its action involves inducing ferroptosis, marked by increased levels of LPO, iron, and ROS. The effectiveness of SS is attributed to compromised antioxidant defenses and mitochondrial damage, crucial factors in the ferroptosis process it triggers [74]. Erianin, a phenolic natural product isolated from Dendrobium chrysotoxum Lindl, has been shown to inhibit the growth of H460 and H1299 cell lines through the induction of Ca2+/calmodulin (CaM)-dependent ferroptotic cell death. This process is accompanied by the formation of ROS, lipid peroxidation, and depletion of GSH [75]. Diplacone (DP), a flavonoid derivative, has been investigated for its capacity to augment mitochondrial calcium influx, ROS generation, the opening of the MPTP, and a reduction of MMP, which are characteristics of ferroptosis. Studies have established that the application of DP to A549 cells not only inhibits cell growth but also enhances lipid peroxidation, a critical step in ferroptosis, along with an increase in ATF3 expression. ATF3 has been identified as playing a role in ferroptosis by regulating the expression of genes involved in iron metabolism and lipid peroxidation. Furthermore, it has been demonstrated that ferroptosis inhibitors, such as ferrostatin-1 and liproxstatin-1, can mitigate DP-mediated cell death in A549 cells. Overall, these findings support the hypothesis that DP can induce ferroptosis in the treatment of NSCLC [76]. The Qingrehuoxue Formula (QRHXF), a two-herb Chinese medicinal formula consisting of Radix Paeoniae Rubra and Scutellaria baicalensis, contains various active compounds including baicalin and paeoniflorin [77, 78]. QRHXF treatment significantly elevates ROS, Fe2+, H2O2, and MDA levels, while reducing GSH levels, indicating its potent effect on oxidative stress. It suppresses the expression of SLC7A11 and GPX4, key ferroptosis markers, and induces changes in the mitochondrial ultrastructure of tumor cells without causing toxicity in tumor-bearing mice. Furthermore, QRHXF upregulates p53 and phospho-glycogen synthase kinase-3 (p-GSK-3β) expressions while downregulating Nrf2 levels. Thus, QRHXF hinders NSCLC cell progression by promoting iron-induced apoptosis and ferroptosis through the p53 and GSK-3β/Nrf2 signaling pathways [78].

Bufotalin, a steroid compound extracted from Venenum Bufonis, has demonstrated significant anticancer properties [79]. Research shows that bufotalin triggers ferroptosis in NSCLC cells through enhanced lipid peroxidation, driven by GPX4 degradation and elevated intracellular Fe2+ levels [32]. Dihydroisotanshinone I (DT), a quinone derivative isolated from the dried roots of Salvia miltiorrhiza Bunge, has shown inhibitory effects on the proliferation of A549, H460, and IMR-90 lung cancer cell lines. Mechanistically, DT inhibits the production of GPX4, thereby initiating ferroptosis via lipid peroxidation [80]. Sanguinarine (SAG), a benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis Linn, exhibited significant inhibitory effects on the growth and metastasis of NSCLC in a xenograft model [81]. SAG destabilizes GPX4 through E3 ligase STUB1-mediated ubiquitination, leading to GPX4 degradation and subsequent ferroptosis [81]. Following this, Red Ginseng Polysaccharide (RGP), polysacchride, an active component of Panax ginseng C. A. Meyer (Araliaceae), has been shown to inhibit the proliferation of human A549 and MDA-MB-231 cells, induce lactate dehydrogenase (LDH) release, promote ferroptosis, and suppress GPX4 expression [82]. Similarly, Timosaponin AIII (Tim-AIII), a steroidal saponin from Anemarrhena Asphodeloides Bunge, induces NSCLC cell death and G2/M arrest. It achieves this therapeutic effect by interacting with its target protein HSP90, facilitating the ubiquitination and subsequent degradation of GPX4, thereby inducing ferroptosis [83]. Zerumbone, a terpenoid compound, primarily extracted from Zingiber zerumbet Smith, acts as an anticancer agent by inhibiting tumor proliferation and promoting cell death [84, 85]. When combined with gefitinib, Zerumbone inhibits lung cancer cell proliferation through multiple mechanisms, including the activation of the AKT/STAT3/SLC7A11 axis, which decreases GPX4 activity and thereby induces ferroptosis [86]. Nrf2 plays a critical role in maintaining cellular redox balance by activating endogenous antioxidant response elements [87]. HO-1 is the primary protein targeted by Nrf2 in the context of oxidative stress. Recent studies have emphasized the importance of Nrf2 and HO-1 in the ferroptotic response. For instance, S-3'-hydroxy-7', 2', 4'-trimethoxyisoxane (ShtIX), a novel flavonoid compound, has been shown to initiate ferroptosis in NSCLC cells by inhibiting the Nrf2/HO-1 signaling pathway [88]. Ginkgetin has been reported to induce ferroptosis in NSCLC by inactivating the Nrf2/HO-1 signaling pathway, thereby enhancing the therapeutic efficacy of cisplatin (DDP) [89]. Additionally, Sanguinarine amplifies MMP loss and DDP-induced apoptosis in NSCLC cells, supporting the potential for combining natural products with chemotherapeutic agents for tumor treatment [72]. Manoalide (MA), a marine terpenoid derived from sponges, has been observed to inhibit the proliferation of KRAS-mutated lung cancer cells and organoids. Notably, MA induces ferroptosis by inhibiting the Nrf2-SLC7A11 axis and ferritin heavy chain 1 (FTH1) pathways, which are activated by excess mitochondrial Ca2+. This enhances the susceptibility of osimertinib-resistant lung cancer cells to osimertinib [90].

In vitro studies have demonstrated that Hedyotis diffusa injection (HDI) can reduce the viability of lung adenocarcinoma cells and induce ferroptosis by modulating VDAC2/3 activity, which is achieved through the upregulation of pro-apoptotic protein Bax and the downregulation of anti-apoptotic protein Bcl2 [91]. Natural borneol (d-borneol), another terpenoid, is extracted from the fresh leaves and branches of Cinnamomum camphora (L.) J. Presl. When combined with cisplatin, d-borneol has been shown to reduce both the volume and weight of tumors, thereby exhibiting anticancer effects. Mechanistically, its role has been linked to ferroptosis, NCOA4-mediated ferritin autophagy, and the upregulation of prion protein (PRNP). Additionally, it leads to the downregulation of Poly(rC)-binding protein 2 (PCBP2), resulting in elevated intracellular iron ion levels [92].

The anti-cancer properties of artemisinin derivatives, such as artesunate (ART) and dihydroartemisinin (DHA), have gained considerable attention in the medical field for their efficacy against various cancers, including lung cancer, colon cancer, nasopharyngeal cancer, and glioma. Both ART and DHA are terpenoid derivatives of artemisinin and have been shown to downregulate the expression of the cystine/glutamate transporter, a critical inhibitor of ferroptosis in NSCLC cells. These compounds primarily induce ferroptosis by upregulating the expression of TFRC, a marker indicative of ferroptosis [93]. Non-coding RNAs, particularly long non-coding RNAs and microRNAs, are implicated in various biological processes, including apoptosis, autophagy, and tumor initiation [94]. FTH1 serves as a marker for ferroptosis. Curcumenol, a terpenoid compound found in Wenyujin, has demonstrated significant anti-cancer properties across various cancer types [95]. Studies have shown that curcumenol-induced ferroptosis is the primary mechanism of lung cancer cell death, both in vitro and in vivo. The lncRNA H19/miR-19b-3p/FTH1 axis plays a crucial role in this ferroptotic cell death induced by curcumenol [96]. Sulforaphane (SFN), a glycoside derived from cruciferous vegetables, has been shown to decrease the expression of SLC7A11, a key component of the system Xc−. This reduction suggests that the anti-tumor effects of SFN may be attributed to the induction of ferroptosis in SCLC cells, potentially due to the downregulation of SLC7A11 at both mRNA and protein levels [97].

Sinapine (SI) is an alkaloid extractable from various rapeseed and cruciferous plant species [98]. Numerous studies have attested to its antioxidant, neuroprotective, anti-inflammatory, and anti-tumor properties [99, 100]. The p53 protein functions as a transcription factor that inhibits cell proliferation and viability, acting as a pivotal tumor suppressor and a ferroptosis regulator [73]. Researchers have confirmed that SI induces ferroptosis in NSCLC cells through a mechanism that involves p53-dependent downregulation of SLC7A11 and upregulation of TF and TFR, ultimately leading to iron accumulation and ferroptosis [101]. HO-3867, a synthetic analog of curcumin (CUR), exhibits potent antitumor activity against various cancer cell types. This compound induces ferroptosis via the activation of the p53-mediated signaling pathway, targeting DMT1 as its downstream effector and concurrently inhibiting the expression of GPX4 [102].

6-Gingerol, a naturally occurring phenol found in ginger, exhibits anti-tumor properties by targeting ubiquitin-specific protease 14 (USP14), a cysteine protease involved in deubiquitination that suppresses autophagy in various cancers. By downregulating USP14, 6-Gingerol enhances autophagosome formation, increases ROS and iron levels, thereby reducing survival, proliferation, and tumor size [103].

KRAS, a key lung tumor growth biomarker, presents a viable target for NSCLC therapies [104]. Activation of the Ras/Raf/ERK pathway is essential for cancer progression. In the caenorhabditis elegans model, realgar, a sulfide mineral from ores, downregulates Ras expression through the Ras/MAPK signaling pathway [105]. Further studies reveal Realgar's potential to inhibit KRAS-mutated lung cancer cell growth by inducing ferroptosis via the Raf-mediated Ras/MAPK pathway [106], positioning it as a promising anti-cancer agent, especially for Ras mutation-targeted ferroptosis.

Curcumin, a phenolic compound from turmeric, is recognized for promoting ferroptosis, particularly in NSCLC, by activating autophagy. This mechanism, linked to the maintenance of cellular iron homeostasis by ferritin [107], suggests that inducing ferroptosis through autophagy can improve NSCLC treatment outcomes [108]. The interplay between autophagy and ferroptosis highlights the potential of leveraging natural products for developing multi-pathway disease treatments.

Anti-cancer immune responses: in-depth exploration have led to the classification of NSCLC, specifically lung squamous carcinoma (LUSC), as an "immunotherapy-responsive disease" [109]. Mutations affecting cellular iron levels within tumor cells have the potential to trigger robust anti-tumor immune responses both in vivo and in vitro, thereby potentially enhancing the efficacy of immune checkpoint inhibitors [110]. Resveratrol, a phenolic compound, concentrated in the peanuts, grapes, knotweed, mulberries, has been shown to induce higher levels of ferroptosis in H520 cells, improve the cytotoxic effects of CD8+ T cells within the tumor microenvironment by modulating the HMMR/ferroptosis axis in cases of LUSC [111]. However, in erastin-induced ferroptosis in BEAS-2B cells, resveratrol promotes GPX4 and GSH expression and protects BEAS-2B cells from ferroptosis via the Nrf2/Keap1 pathway [112].

To summarize, the reviewed studies demonstrate the efficacy of 8 natural products from herbs—flavonoids, phenols, alkaloids, terpenoids, steroids, quinones, polysaccharides, and glycosides—comprising 21 active ingredients. These compounds modulate ferroptosis, inhibit tumor growth, invasion, metastasis, and enhance cancer survival. They induce ferroptosis through mechanisms like increased GPX4 ubiquitination, GPX4 and GSH depletion, calcium channel activation leading to calcium overload, iron metabolism enhancement, ferritin autophagy initiation, Fenton reaction, mitochondrial membrane disruption, ROS release, and lipid peroxidation. Key pathways include GPX4-related, SLC7A11-related, VDAC-mediated, p53-mediated, Nrf2-mediated, and NCOA4-mediated mechanisms. But it should be noted that balancing the effects of ferroptosis-modulating drugs on cancerous versus healthy tissues remains a significant challenge.

ALI is a critical condition that may manifest as a severe form of ARDS or part of Multiple Organ Dysfunction Syndrome (MODS). It’s typically marked by uncontrolled oxidative stress, pulmonary inflammation, damage to the alveolar and microvascular endothelia, and pulmonary edema [113], with the potential to evolve into ARDS and MODS. Current treatment modalities for ALI primarily include nutritional support, mechanical ventilation, etiological treatment, symptomatic relief, and maintenance of internal homeostasis, supplemented with glucocorticoid hormone, inhaled pulmonary vasodilator, nerve muscle blocker [114, 115]. Given the high morbidity and mortality associated with ALI, there's a pressing need for new therapeutic approaches. Recent research highlights that bioactive compounds from Chinese herbs and their extracts could offer new pathways to mitigate ALI/ARDS. Notably, increased iron accumulation has been observed in the lungs of mice suffering from ALI. Excessive iron promotes the generation of superoxide and induces lipid peroxidation through the Fenton reaction, ultimately triggering ferroptosis [66]. Ferroptosis has been implicated in several models of ALI, including those induced by lipopolysaccharide (LPS), intestinal ischemia/reperfusion (I/R), seawater drowning, fine particulate matter (PM2.5), oleic acid, and Pseudomonas aeruginosa (PA) [13]. We collected relevant lung injury studies and found that inhibition of ferroptosis has a significant effect on the treatment of ALI.

Nrf2, a key transcription factor, is essential in regulating cellular antioxidant defenses and plays a vital role in mitigating ALI by preventing ferroptosis. Its activation leads to a decrease in GSH depletion and an increase in the expression of oxidative stress-related factors, including hypoxia-inducible factor 1α (HIF-1α) and HO-1. This activation subsequently inhibits the accumulation of MDA, ROS, and lipid ROS, enhances mitochondrial structure and function, reduces ferroptosis, and alleviates ALI [89, 116]. HIF-1α plays a crucial role in bolstering anti-ferroptotic defenses, reducing iron accumulation, and boosting GPX4 expression [117]. The Nrf2/HO-1 signaling pathway is pivotal in controlling cellular damage caused by various factors, with its activation offering protection against tissue and cellular damage through diverse mechanisms [118]. SLC7A11, also known as xCT, alleviates oxidative stress in epithelial cells by enhancing intracellular cystine levels, acting as a negative feedback loop to restrain the Nrf2/HO-1 pathway, thus preserving cellular antioxidant balance [119]. Collectively, these studies unequivocally establish that Nrf2 serves as a major negative regulator of ferroptosis in ALI, and that ferroptosis itself contributes to the progression of ALI. In this review, we summarize the mechanisms by which natural products treat ALI through the regulation of ferroptosis, as detailed in Table 2.

Astaxanthin (AST) is a xanthophyll carotenoid belonging to the terpenoids class, found in various microorganisms, phytoplankton, marine animals, and seafood [120]. Luo et al. investigated LPS-induced RAW264.7 cells and mice with ALI and discovered that Astaxanthin mitigated inflammatory responses, inhibited ferroptosis, and ameliorated lung damage through the activation of the Keap1-Nrf2/HO-1 pathway [121]. Panax ginseng is a well-known botanical species utilized in traditional medicine for its detoxifying properties, blood glucose regulation, prevention of arteriosclerosis, and potential anti-aging effects [119, 122]. The pharmacological efficacy of ginseng is primarily attributed to its polyacetylene compounds. Panaxydol (PX) is a polyacetylene molecule that has been extensively studied for its diverse biological properties, including anti-fatigue, anti-tumor, and neuroprotective effects [123,124,125]. In the LPS-induced mouse lung injury model, endotoxin infection increases alveolar capillary permeability, leading to fluid and protein leakage into the alveoli, which causes pulmonary edema and lung tissue damage. These conditions show improvement following PX intervention. Further, PX effectively mitigates LPS-induced ferroptosis in ALI through the Keap1-Nrf2/HO-1 pathway, suggesting its potential as a novel therapeutic option for ALI treatment [30]. Urolithin A (UA) is a secondary metabolite derived from the gut microbiome metabolism of ellagitannins and ellagic acid, which are abundant in pomegranates, strawberries, and various nuts [126, 127]. UA, a phenolic compound, significantly reduced histological alterations, the wet-to-dry lung weight ratio, and the invasion of inflammatory cells, thereby offering protection against LPS-induced ALI in mice. The underlying mechanism involves the activation of the Keap1-Nrf2/HO-1 pathway, which subsequently elevates antioxidant levels in lung tissue and reduces ferroptosis [128]. Obacunone (OB) is a naturally occurring flavonoid commonly found in citrus fruits and is known for its anti-inflammatory and antioxidant properties [129, 130]. Research demonstrated that OB significantly mitigated lung histopathological injury, reduced the release of inflammatory cytokines, and decreased levels of Fe2+ and 4-HNE, by inhibiting Nrf2 ubiquitination and upregulating the Nrf2/SLC7A11/GPX4 signaling pathway, ultimately inhibiting iron-dependent ferroptosis and alleviating LPS-induced ALI [131].

Wedelolactone (Wed) is the principal active component of Eclipta prostrata and is categorized as a lactone [132]. Research findings indicate that Wed mitigates pancreatitis and associated lung damage in mouse models induced by taurine cholate or small proteins. Specifically, Wed inhibits cell death and ferroptosis in pancreatic and pancreatic acinar cells by upregulating GPX4 [133]. Qingyi decoction (QYD) is a robust anti-inflammatory agent that can improve the intestinal barrier damage caused by SAP, microcirculatory disorders, and pulmonary inflammatory response and has been shown to inhibit both ferroptosis and apoptosis by enhancing the activity of Aldehyde Dehydrogenase 2 (ALDH2). This suggests that QYD has potential therapeutic efficacy in treating lung injury related to severe acute pancreatitis (SAP). Originating from the formula in "Shanghan Lun," as a decoction made from Chinese herbal medicine, QYD is employed in the treatment of acute pancreatitis (AP) patients due to its laxative, heat-clearing, and detoxifying properties [134, 135]. Uncoupling Protein-2 (UCP2) is crucial for managing ROS, maintaining redox balance, and modulating immune responses. Research shows that matrine, an alkaloid from Sophora flavescens, reduces inflammation, oxidative stress, and iron buildup in lung tissue during severe acute pancreatitis-induced acute lung injury (SAP-ALI) by activating the UCP2/SIRT3/PGC1α pathway, highlighting matrine's therapeutic potential for SAP-ALI management [136].

Exposure to PM2.5 has been linked to a multitude of respiratory diseases and was responsible for over 4.2 million deaths in 2015 [137]. Various studies have indicated that PM2.5-induced lung damage is associated with ferroptosis through multiple signaling pathways. One such pathway, the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), is instrumental in regulating the activation of Nrf2, which in turn mitigates lung injury. Sipeimine, a steroidal alkaloid extracted from Fritillaria roylei, possesses significant pharmacological attributes, including anti-inflammatory, antitussive, and anti-asthmatic effects [138, 139]. The primary mechanism by which sipeimine ameliorates PM2.5-induced ALI is predominantly through the PI3K/Akt/Nrf2 pathway. This leads to the attenuation of ferroptosis and the restoration of downregulated proteins involved in ferroptosis, such as GPX4, HO-1, and SLC7A11 [140]. Tectoridin, a flavonoid from the rhizome of Belamcanda chinensis, activates the Nrf2 signaling pathway to prevent ferroptosis in lung damage [