Ferroptosis-Regulated Natural Products and miRNAs and Their Potential Targeting to Ferroptosis and Exosome Biogenesis

Ferroptosis, which comprises iron-dependent cell death, is crucial in cancer and non-cancer treatments. Exosomes, the extracellular vesicles, may deliver biomolecules to regulate disease progression. The interplay between ferroptosis and exosomes may modulate cancer development but is rarely investigated in natural product treatments and their modulating miRNAs. This review focuses on the ferroptosis-modulating effects of natural products and miRNAs concerning their participation in ferroptosis and exosome biogenesis (secretion and assembly)-related targets in cancer and non-cancer cells. Natural products and miRNAs with ferroptosis-modulating effects were retrieved and organized. Next, a literature search established the connection of a panel of ferroptosis-modulating genes to these ferroptosis-associated natural products. Moreover, ferroptosis-associated miRNAs were inputted into the miRNA database (miRDB) to bioinformatically search the potential targets for the modulation of ferroptosis and exosome biogenesis. Finally, the literature search provided a connection between ferroptosis-modulating miRNAs and natural products. Consequently, the connections from ferroptosis–miRNA–exosome biogenesis to natural product-based anticancer treatments are well-organized. This review sheds light on the research directions for integrating miRNAs and exosome biogenesis into the ferroptosis-modulating therapeutic effects of natural products on cancer and non-cancer diseases.

Ferroptosis comprises iron-dependent non-apoptotic cell death characterized by the overexpression of membrane lipid peroxidation, an increase in cellular iron uptake, and the triggering of ferroptosis signaling [7].Modulating ferroptosis is an anticancer strategy [8,9].Ferroptosis-inducing compounds may improve pharmaceutical effects with respect to inhibiting metastasis, drug resistance, and tumor regression [9].

Figure 1.
The rationale of ferroptosis-modulating miRNAs of ferroptosis-modulating natural products and their potential targeting of ferroptosis and exosome biogenesis modulation.There are two knowledge gaps for the natural product-miRNA-ferroptosis/exosome biogenesis target axis.The first knowledge gap is the disconnection between the modulating effects of miRNAs and natural products acting on ferroptosis.The second knowledge gap is disconnection between the ferroptosisand exosome-biogenesis-modulating targets and natural-product-regulated miRNAs.This review focuses on retrieving natural products with ferroptosis-modulating effects.The involvement of miR-NAs in ferroptosis-modulating natural products is explored by Google Scholar to fill the first gap.To fill the second gap, these ferroptosis-modulating miRNAs are used to retrieve the potential targets for ferroptosis and exosome biogenesis by utilizing Google Scholar and the miRDB database.Notably, the modulations of ferroptosis and exosome biogenesis are based on miRDB retrieval to identify the possible targets for ferroptosis and exosome biogenesis by these ferroptosis-modulated miRNAs.Ferroptosis-inducing genes, ferroptosis-inhibiting genes, and exosome-biogenesis-modulating genes are mentioned (Sections 1.2, 1.3.1 and 1.3.2).Consequently, the rationale for the natural product-miRNA-ferroptosis/exosome biogenesis target axis is established.

Ferroptosis-Modulating Genes
Several ferroptosis-modulating genes, such as 25 ferroptosis-inducing genes and 24 ferroptosis-inhibiting genes, are collected in this review.These ferroptosis-modulating genes (Figure 1) are used as candidates for determining the potential regulation of ferroptosis by carrying out a literature search (PubMed and Google Scholar) and bioinformatic data-mining (miRDB) [19].

Ferroptosis-Modulating Genes
Several ferroptosis-modulating genes, such as 25 ferroptosis-inducing genes and 24 ferroptosis-inhibiting genes, are collected in this review.These ferroptosis-modulating genes (Figure 1) are used as candidates for determining the potential regulation of ferroptosis by carrying out a literature search (PubMed and Google Scholar) and bioinformatic data-mining (miRDB) [19].

The Knowledge Gaps of miRNA-Modulating Natural Products for the Induction and Inhibition of Ferroptosis and Exosome Biogenesis
Several natural products were evaluated, and they demonstrated the modulation function for exosomal miRNAs and exosome biogenesis [30].However, this exosomal miRNA review did not consider the impact of ferroptosis in natural product studies.
Several literature reports have recently organized comprehensive ferroptosis-modulating natural products [31][32][33][34].For example, the effects of various natural products exhibiting inducing and inhibiting effects on ferroptosis in several diseases and cancers have been summarized [31,32].Their functional targets and experimental models for these ferroptosismodulating natural products are demonstrated.In comparison, the chemical structures of ferroptosis-modulating natural products are presented but do not discuss the target genes of ferroptosis [32,34].Another review provides information on the compound source, cell line names, concentration, and treatment time of natural products with ferroptosis, necroptosis, and pyroptosis-inducing ability [33].However, these reviews summarize ferroptosismodulating natural products without considering the impact of miRNAs [31][32][33][34].
As mentioned, those studies of ferroptosis-modulating natural products and miRNAs were individually investigated without exploring their relationships.A knowledge gap was discovered in the connection between the modulating effects of miRNAs and natural products acting on ferroptosis.Moreover, there is another knowledge gap: the ferroptosisand exosome-biogenesis-modulating targets of natural products-regulated miRNAs were limitedly reported.Hence, comprehensive assessments of natural product studies targeting the modulation of ferroptosis and exosome biogenesis by miRNAs are warranted.

The Novelty, Rationale, and Outline of This Review
Several reviews have specific scopes for natural products, miRNAs, exosome biosynthesis, or ferroptosis, but the connection between them is weakly emphasized and organized.The novelty of the current review is to fix these disconnections by introducing bioinformatics retrieval and deep literature searches.
Many types of cell death play differential roles in anticancer responses [38,39].Interestingly, ferroptosis comprises iron-dependent non-apoptotic cell death.Switching from apoptosis to ferroptosis may improve the anticancer effects against cancer stem cells [40].Moreover, many natural products exhibit modulating effects on ferroptosis.Therefore, this review focuses on ferroptosis-associated responses involving natural products.The rationale of this review is to propose a regulatory axis where ferroptosis-modulating natural products affect ferroptosis-modulating miRNAs, which in turn control ferroptosis-and exosome-biogenesis-modulating targets (Figure 1).Those two gaps are innovatively filled in this review as described below.
In this review, several ferroptosis-modulating natural products and their potential role of modulating ferroptosis signaling were overviewed by a literature search (PubMed and Google Scholar) (Section 2).There is a knowledge gap with respect to the connections between the modulating effects of the miRNA of natural products and ferroptosis and exosome biogenesis (Figure 1).To fill this gap, we performed a literature search (PubMed and Google Scholar) and bioinformatic database mining (miRDB) that allowed ferroptosis-modulating miRNAs and their potential ferroptosis-targeting genes to be re-trieved (Section 3).Similarly, ferroptosis-modulating miRNAs and their potential exosome biogenesis-targeting genes were retrieved (Section 4).
Another gap is the connection between ferroptosis-modulating natural products and miRNAs because they were individually reported (Figure 1).After the literature search, the relationship between ferroptosis-modulating miRNAs and some natural products was explored to fill this gap (Section 5).Consequently, this review provides the connecting information between the potential modulation of miRNAs and exosome biogenesis in ferroptosis-modulating natural products.
The Google Scholar search methodology for ferroptosis-modulating natural products was performed as follows: Based on the search term "natural products ferroptosis", only pure compounds are included for natural products with ferroptosis-modulating effects (inducing and inhibiting) (Table 1), whereas the crude extracts are excluded.Moreover, the ferroptosisinducing and inhibiting genes (as described in Figure 1 or Sections 1.3.1 and 1.3.2) regulated by these natural products are also retrieved by Google Scholar.

Ferroptosis-Inducing Natural Products
Several natural products are potential ferroptosis inducers (Table 1).Although the review focuses on ferroptosis, some ferroptosis-inducing natural products with ferroptotic and non-ferroptotic effects are mentioned.Some reviews on ferroptosis-inducing natural products did not examine ferroptosis but showed the impact of ferroptosis by the modulation of ferroptosis-inducing or ferroptosis-inhibiting genes.
Generally, natural products upregulating the ferroptosis-inducing genes or downregulating the ferroptosis-inhibiting genes are potential ferroptosis inducers (Figure 2).The ferroptosis-inducing natural products and miRNAs were retrieved by a literature search (PubMed and Google Scholar), while potential targets of ferroptosis-inducing RNAs were retrieved from the miRDB database [19].The ferroptosis-inducing functions of the reported natural products and their modulations (inducing or inhibiting) on ferroptosis-inducing or ferroptosis-inhibiting targets are exemplified as follows (Table 1).Natural products that modulate specific proteins in the molecular pathway of inducing ferroptosis are shown (Figure 3).Generally, natural products upregulating the ferroptosis-inducing genes or downregulating the ferroptosis-inhibiting genes are potential ferroptosis inducers (Figure 2).The ferroptosis-inducing natural products and miRNAs were retrieved by a literature search (PubMed and Google Scholar), while potential targets of ferroptosis-inducing RNAs were retrieved from the miRDB database [19].The ferroptosis-inducing functions of the reported natural products and their modulations (inducing or inhibiting) on ferroptosis-inducing or ferroptosis-inhibiting targets are exemplified as follows (Table 1).Natural products that modulate specific proteins in the molecular pathway of inducing ferroptosis are shown (Figure 3).Natural products that modulate specific proteins in the molecular pathway of inducing and inhibiting ferroptosis.This pathway is drawn by considering the information from many literature reports [173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189].Natural products that target these specific proteins have been described in Table 1.The ferroptosis-inducing and inhibiting natural products are indicated in black and red, respectively.Although these natural products potentially target the ferroptosis signaling pathway, their potential impact on ferroptosis still warrants detailed investigation.The ferroptosis-inducing and inhibiting targets (as described in Sections 1.
Artesunate may demonstrate both the upregulation of ferroptosis-inducing genes and the downregulation of ferroptosis-inhibiting genes associated with ferroptosis and/or other non-ferroptosis responses (Table 1).Artesunate induces ferritinophagy-mediated ferroptosis and the anti-fibrosis effects of activated hepatic stellate cells by upregulating the ferroptosis-inducing ATG5 gene and downregulating ferroptosis-inhibiting FTH1 gene [47].Notably, the participation of ferroptosis in these natural products still warrants further assessment.

Albiziabioside A and Alloimperatorin
The responses of the upregulation of ferroptosis-inducing genes and/or the downregulation of ferroptosis-inhibiting genes were also reported in several ferroptosis-inducing natural products, such as albiziabioside A and alloimperatorin (Table 1).Albiziabioside A triggers the ferroptosis of colon cancer cells, which is associated with apoptosis [50].Similarly, albiziabioside A induces the apoptosis and ferroptosis of breast cancer cells, accompanied by the downregulation of the ferroptosis-inhibiting GPX4 gene [51].For alloimperatorin, it induces the antiproliferation, apoptosis, and ferroptosis of breast cancer cells by downregulating the ferroptosis-inhibiting genes (SLC7A11, GPX4, and phosphorylated AIFM1) [24].The detailed impacts of these natural products on ferroptosis still warrant further assessment.

Curcumin
In the case of the upregulation of ferroptosis-inducing genes, several curcumin studies demonstrate the induction of ferroptosis (Table 1).Curcumin enhances the ferroptosis of lung cancer cells by upregulating the ferroptosis-inducing ACSL4 gene [64].Curcumin promotes ferroptosis, thereby inhibiting lung cancer tumor growth, by upregulating ACSL4 and downregulating ferroptosis-inhibiting genes (SLC7A11 and GPX4) [64].In addition to ferroptosis, curcumin promotes the autophagy of lung cancer cells, and this is alleviated by downregulating the ferroptosis-inhibiting IREB2 gene [63].This suggests that curcumininduced ferroptosis and autophagy are associated with the upregulation of IREB2.
In the case of the downregulation of ferroptosis-inhibiting genes, several curcumin studies demonstrate the induction of ferroptosis (Table 1).Curcumin promotes the antiproliferation and ferroptosis of the colon [62] and lung [64] cancer cells by downregulating ferroptosis-inhibiting genes (SLC7A11 and GPX4).Without assessing ferroptosis, curcumin modulates non-ferroptosis effects such as tumor neovascularization [66] and migration [67,68] by downregulating ferroptosis-inhibiting genes (Table 1).Curcumin inhibits the gene expression of tumor neovascularization, such as that of the ferroptosisinhibiting HIF1A gene, in pituitary adenomas [66].Curcumin suppresses the proliferation and migration of prostate [68] and glioma [67] cancer cells by inhibiting the expression of the ferroptosis-inhibiting NEDD4 gene.

Dihydroartemisinin, Dihydroisotanshinone I, and DMOCPTL
The upregulation of ferroptosis-inducing genes and/or the downregulation of ferroptosisinhibiting genes were demonstrated in several ferroptosis-inducing natural products, such as dihydroartemisinin, dihydroisotanshinone I, and DMOCPTL (Table 1).
Dihydroartemisinin, a common artemisinin derivative, triggers the ferroptosis of several cancer and non-cancer cells (Table 1).In cancer cell studies, dihydroartemisinin inhibits proliferation and migration and triggers the ferroptosis of glioma cells by upregulating the ferroptosis-inducing HMOX1 gene and downregulating the ferroptosis-inhibiting GPX4 gene [69].Dihydroartemisinin promotes the antiproliferation and ferroptosis of liver cancer cells by upregulating the ferroptosis-inducing ATF4 gene and downregulating ferroptosis-inhibiting genes (GPX4, SLC7A11, and SLC3A2) [70].In non-cancer cell studies, dihydroartemisinin triggers the ferroptosis of hepatic stellate cells by upregulating the ferroptosis-inducing NCOA4 gene [72].Moreover, dihydroartemisinin also induces a non-ferroptosis response, such as ER stress.Dihydroartemisinin also induces the ER stress of porcine ovarian granulosa cells by upregulating the ferroptosis-inducing ATF4 gene [71].However, its impact on the regulation of ferroptosis warrants a detailed assessment.
Dihydroisotanshinone I suppresses proliferation and induces the ferroptosis of glioma cells by upregulating the ferroptosis-inducing ACSL4 gene and downregulating the ferroptosisinhibiting GPX4 gene [74] (Table 1).Moreover, DMOCPTL, a derivative of the natural product parthenolide, induces the apoptosis and ferroptosis of breast cancer cells by directly binding to GPX4 and causing degradation of GPX4 [76].The impacts on ferroptosis of these natural products still warrant further investigation.
In contrast, EGCG may downregulate ferroptosis-inhibiting genes (Table 1).Without assessing ferroptosis, EGCG modulates non-ferroptosis effects such as apoptosis.EGCG suppresses proliferation and causes the apoptosis of oral cancer cells by downregulating the ferroptosis-inhibiting TP53 gene [81].Moreover, EGCG also downregulates the ferroptosisinhibiting SP1 gene in terms of molecular docking experiments [81].The ferroptosis response of these non-ferroptosis studies of EGCG warrants a detailed investigation.
Ferroptocide, a novel compound derived from pleuromutilin, promotes the ferroptosis of ovarian cancer cells [23] (Table 1).Ferroptocide is also a TXN inhibitor [23] with the potential to inhibit antioxidant systems and cause oxidative stress, but its ferroptotic effects warrant a detailed assessment.
2.1.9.Piperlongumine and Pseudolaric Acid B Similar ferroptosis modulation is attributed to piperlongumine and pseudolaric acid B (Table 1).Piperlongumine triggers the ferroptosis and cell death of pancreatic cancer cells [94].Piperlongumine has been reported to show anticancer effects by modulating ferroptosis inducers and inhibitors, but the impact of ferroptosis was not assessed.For example, piperlongumine induces the apoptosis of liver cancer cells by upregulating the ferroptosis-inducing ATF4 gene [95].Piperlongumine promotes the apoptosis of pancreatic cancer cells by upregulating the ferroptosis-inducing HMOX1 gene [96].Piperlongumine shows the antiproliferation of oral cancer cells by downregulating ferroptosis-inhibiting genes (FTH1, SLC7A11, and GPX4) [97].Piperlongumine downregulates the ferroptosisinhibiting SP1 gene in kidney cancer cells [98].Since the expressions of these ferroptosis inducers and inhibitors have changed, a detailed evaluation of ferroptosis induction in these cancer studies treated with piperlongumine is warranted.Moreover, pseudolaric acid B induces the antiproliferation and ferroptosis of glioma cells by downregulating the ferroptosis-inhibiting SLC7A11 gene [99].

Quercetin
Several quercetin studies demonstrate the upregulation of ferroptosis-inducing genes (Table 1).Quercetin promotes the ferroptosis of breast cancer cells by improving the lysosomal degradation of ferritin (FTH1 and FTL), which are ferroptosis-inhibiting proteins [101].Quercetin was reported to upregulate several ferroptosis-inducing genes, but the impact of ferroptosis was not assessed.For example, quercetin enhances macrophage M2 polarization by inducing the expression of the ferroptosis-inducing ATF3 gene [102].Quercetin promotes lipopolysaccharide (LPS)-influenced NO generation to alleviate the inflammatory responses of microglial cells by upregulating the ferroptosis-inducing HMOX1 gene [103].This warrants a detailed investigation of the ferroptosis responses of the above quercetin studies.
In contrast, quercetin was reported to downregulate ferroptosis-inhibiting genes (SP1 [104], SLC40A1 [104], and FTL [105]), but the impact of ferroptosis was not assessed.In a cancer study, quercetin causes the antiproliferation and apoptosis of malignant pleural mesothelioma by inhibiting the expression of the ferroptosis-inhibiting SP1 gene [106].In non-cancer studies, quercetin downregulates the ferroptosis-inhibiting SLC40A1 gene of colon cancer cells and reduces intestinal iron absorption in rats [104].Similarly, quercetin reduces alcohol-fed mice's liver damage and iron levels by downregulating FTL [105].In contrast, other ferroptosis events are rarely investigated in these studies [104,105].An assessment of the impact of quercetin treatments on ferroptosis is warranted in these studies.
Solasonine, a Solanum melongena-derived natural product, inhibits proliferation and promotes the ferroptosis of liver cancer cells by downregulating ferroptosis-inhibiting genes (GPX4 and GSS) [119].Without assessing ferroptosis, solasonine induces cancer cell proliferation by downregulating ferroptosis-inhibiting genes.Solasonine inhibits the proliferation of pancreatic cancer cells by downregulating the ferroptosis-inhibiting SLC7A11 gene in a ubiquitination-degradation manner [120].The impact of ferroptosis on this solasonine study needs further assessment.
For comparison, without assessing ferroptosis, salinomycin induces non-ferroptotic effects, such as ER stress [114] and apoptosis [114][115][116], by downregulating ferroptosisinhibiting genes (Table 1).Salinomycin triggers ER stress and the apoptosis of prostate cancer cells, and this is associated with the downregulation of ferroptosis-inhibiting genes (NFE2L2 and GCLC) [114].Salinomycin decreases the proliferation and promotes the apoptosis of endometrial cancer cells by downregulating the ferroptosis-inhibiting HIF1A gene [115].Salinomycin induces the apoptosis of liver cancer cells by downregulating the ferroptosis-inhibiting TP53 gene [116].Additionally, salinomycin is reported to be a SLC11A2 inhibitor in cancer stem cells by upregulating iron homeostasis [191].
Without assessing ferroptosis, sulforaphane induces non-ferroptotic effects, such as autophagy [123] and apoptosis [123,124], by modulating ferroptosis-inducing or inhibiting genes (Table 1).Sulforaphane induces the autophagy and apoptosis of hepatoblastoma cells, associated with the upregulation of the ferroptosis-inducing ATG7 gene [123].Sulforaphane induces the apoptosis of cervical cancer cells by enhancing the ferroptosis-inducing ALOX12 gene and inhibiting the expression of the ferroptosis-inhibiting GPX4 gene [124].
Some sulforaphane reports also regulate ferroptosis-modulating genes without assessing ferroptosis responses.Sulforaphane inhibits the proliferation of head and neck cancer cells by upregulating the ferroptosis-inducing HMOX1 gene [125].Sulforaphane inhibits the proliferation of cancer stem cells by upregulating the ferroptosis-inducing YAP1 gene [126].The impact of ferroptosis on these solasonine studies needs further assessment.

Other Ferroptosis-Inducing Natural Products
Some natural products (Table 1) also demonstrate ferroptosis-inducing effects, but their potential ferroptosis-modulating targets could not be retrieved by a literature search.For example, ardisiacrispin B induces the apoptosis and ferroptosis of breast cancer cells [54].Aridanin [55], artenimol [59], and epunctanone [82] induce the antiproliferation and ferroptosis of leukemia cells, and this is reversed by ferroptosis-inhibiting genes.Diplacone, a Paulownia tomentosa fruit-derived natural product, causes the antiproliferation and ferroptosis of lung cancer cells [75].Punicic acid, a main bioactive component in pomegranate seed oil, exhibits antiproliferation and triggers ferroptosis in colon cancer cells [100].Typhaneoside inhibits the proliferation of acute myeloid leukemia (AML) by upregulating ferroptosis and autophagy [130].Ungeremine inhibits the proliferation of leukemia cells by inducing apoptosis, ferroptosis, necroptosis, and autophagy [131].This warrants advanced experiments to explore potential ferroptosis-modulating targets in the future.

Ferroptosis-Inhibiting Natural Products
Many natural products are potential ferroptosis-inhibiting genes (Table 1).Although this review focuses on ferroptosis, some ferroptosis-inhibiting natural products exhibiting ferroptotic and non-ferroptotic effects are mentioned.Some studies on ferroptosis-inhibiting natural products did not examine ferroptosis but showed the impact of ferroptosis due to the modulation of ferroptosis-inhibiting genes.
In general, natural products upregulate ferroptosis-inhibiting genes or downregulate ferroptosis-inducing genes (Figure 2).The ferroptosis-inhibiting natural products and miR-NAs were retrieved by a literature search (PubMed and Google Scholar), while the potential targets of ferroptosis-inhibiting RNAs were retrieved from the miRDB database [19].The ferroptosis-inhibiting functions of reported natural products and their modulation (inducing or inhibiting) on ferroptosis-inducing or ferroptosis-inhibiting targets are exemplified as follows (Table 1).Natural products that modulate specific proteins in the molecular pathway of inhibiting ferroptosis are shown (Figure 3).The modulating effects of ferroptosis-inhibiting natural products, such as nodosin, nordihydroguaiaretic acid, and cryptotanshinone, are reported in cancer studies (Table 1).Nodosin and nordihydroguaiaretic acid inhibit ferroptosis by regulating ferroptosis-modulating genes.Nodosin inhibits the migration of bladder cancer by inhibiting ferroptosis [142].Nodosin promotes the expression of the ferroptosis-inhibiting AIFM2 gene, and in turn, AIFM2 interacts with the ferroptosis-inhibiting GPX4 protein to inhibit lipid peroxidation and ferroptosis [142].Nordihydroguaiaretic acid, an inhibitor of the ferroptosis-inducing proteins ALOX12/15, alleviates the GPX4 inhibitor (RLS3)-triggered ferroptosis of acute lymphoblastic leukemia cells [143], suggesting nordihydroguaiaretic acid as a ferroptosis inhibitor.Cryptotanshinone, a Salvia miltiorrhiza-derived diterpenoid anthraquinone, suppresses erastin-induced ferroptosis and the cell death of pancreatic cancer cells [144].However, its regulation on ferroptosis-modulating genes is rarely investigated.

Cancer and Non-Cancer Studies for Ferroptosis-Inhibiting Natural Products
The modulating effects of ferroptosis-inhibiting natural products, such as artepillin C, bakuchiol, glycyrrhizin, psoralidin, and baicalein, are reported in both cancer and non-cancer studies (Table 1).

Artepillin C and Bakuchiol
Several natural products demonstrate neuroprotective and neuron-related tumor regression effects by downregulating ferroptosis (Table 1).Artepillin C, a natural product derived from Brazilian green propolis, was shown to have anticancer (neurofibromatosisassociated tumors) impacts [195].For the non-cancer study, artepillin C exhibits neuroprotective effects on mouse hippocampal HT22 cells by downregulating ferroptosis [145].Bakuchiol, a Cullen corylifolium-derived natural product, shows antiproliferative effects on skin cancer cells [196], but the impact of ferroptosis is not assessed.In comparison, the potential ferroptosis of bakuchiol was reported in non-cancer cells.For example, bakuchiol suppresses the erastin-triggered ferroptosis of mouse hippocampal cells [146].The impact of ferroptosis on these artepillin C and bakuchiol studies needs to be further assessed.

Berberine
Berberine studies showing similar ferroptosis modulation (upregulation and downregulation) are exemplified (Table 1).Berberine alleviates erastin and RSL3 (GPX4 inhibitor)triggered cell death and the ferroptosis of cardiac cells [147].Berberine exhibits anticancer effects, such as breast cancer cells [197], but the participation of ferroptosis is not assessed.
Psoralidin suppresses the ferroptosis of hippocampal cells based on an erastin-induced ferroptosis-mediated cell viability assay [146].Psoralidin exerts tumor-growth-suppressing effects based on a breast cancer cell xenografted mouse model [199].However, the impact of ferroptosis was not assessed.
Butein alleviates the erastin-induced ferroptosis of bone-marrow-derived mesenchymal stem (BMSCs) cells via its antioxidant properties [155].Notably, butein may regulate non-ferroptosis responses.Butein triggers apoptosis and suppresses the migration of liver cancer cells by upregulating the ferroptosis-inhibiting SP1 gene [156].The role of ferroptosis in these non-ferroptosis studies needs to be further validated.

Non-Cancer Studies for Ferroptosis-Inhibiting Natural Products
The modulating effects of ferroptosis-inhibiting natural products are reported in noncancer studies (Table 1).
Detailed investigation of the regulation of exosome biogenesis by the remaining ferroptosis-modulating natural products is warranted.The potential impact on exosome biogenesis by ferroptosis-modulating natural products is discussed later.
The Google Scholar search methodology for ferroptosis-modulating miRNAs and their target genes is described as follows: Based on the search term "miRNA ferroptosis", only those miRNAs with identified complete names showing 3p or 5p information are included if available (Table 2).Then, this complete name information for miRNAs is suitable for an miRDB-targeted search for the modulation of ferroptosis bioinformatically.

Ferroptosis-Inducing miRNAs and Their Ferroptosis-Targeting Genes
miRNAs can bind to their target and downregulate target expression.The rationale is that ferroptosis-inducing miRNAs are expected to target ferroptosis-inhibiting genes (Figure 2).Different ferroptosis miRNAs may have the same targets.Many ferroptosisinducing miRNAs and targets from literature reports and miRDB mining were exemplified in the order of target genes (Table 2).
In addition to SLCA11, other potential targets for miR-25-3p are AIFM1 and SCL11A2; GCLC and SLC11A2 are potential targets for miR-27-3p; NEDD4 and NFE2L2 are potential targets for miR-545-3p; and TXNRD1 is a potential target for miR-205-5p (Table 2).All these potential miRDB-targets are ferroptosis-inhibiting genes that are possibly downregulated by these ferroptosis-inducing miRNAs.This warrants a detailed examination of the participation of these ferroptosis-inhibiting genes in studies for ferroptosis-inducing miRNAs.
In addition to SLC40A1, another potential miRDB target for miR-302a-3p is AIFM1, while those for miR-4735-3p include HIF1A, NEDD4, and GCLC (Table 2).SLC7A11 is retrieved by performing an miRDB search.These potential miRDB targets are ferroptosisinhibiting genes that are possibly downregulated by ferroptosis-inducing miRNAs as described.This warrants a detailed assessment of the participation of these ferroptosisinhibiting genes in these ferroptosis-inducing miRNA experiments.

Ferroptosis-Inhibiting miRNAs and Their Ferroptosis-Targeting Genes
miRNAs can bind to their target and downregulate target expression.The rationale is that ferroptosis-inhibiting miRNAs are expected to target ferroptosis-inducing genes (Figure 2).Several ferroptosis-inhibiting miRNAs and targets from literature reports and miRDB mining (Table 2) are exemplified in the order of target genes.

Ferroptosis-Modulating miRNAs and Their Exosome-Biogenesis-Targeting Genes
The ferroptosis-inducing exosomal miRNAs are summarized in Table 2.However, the potential regulations of the exosome biogenesis function of these miRNAs are not investigated in the literature reports listed in Table 2. Using the literature search (PubMed and Google Scholar), the participation of these ferroptosis-inducing (Sections 4.1 and 4.2) and ferroptosis-inhibiting (Sections 4.3 and 4.4) exosomal miRNAs in exosome studies were retrieved (Table 3).Similarly, the potential functions of these ferroptosis-inducing and ferroptosis-inhibiting exosomal miRNAs in modulating exosome biogenesis are investigated by performing miRDB, which is a robust database for providing miRNA targets (Table 3).Moreover, several anti-cancer and non-cancer studies have reported the impacts of several ferroptosis-inducing (Sections 4.1 and 4.2) and ferroptosis-inhibiting (Sections 4.3 and 4.4) exosomal miRNAs on exosome biogenesis, although they did not assess the ferroptosis-modulating effects.The detailed information on these concerns is mentioned as follows.
The Google Scholar search methodology for ferroptosis-modulating miRNAs and their exosome biogenesis target genes is described as follows: Ferroptosis-modulating miRNAs listed in Table 2 were combined with "exosome" for the search to obtain the results for "exosomal miRNA studies" (Table 3).Then, this complete name information for miRNAs was suitable for an miRDB-targeted search for the modulation of exosome biogenesis bioinformatically.
Some exosomal miRNAs are reported to modulate angiogenesis.For example, the migration and proliferation of trophoblasts are improved, and the angiogenesis of HUVEC is inhibited, by exosomal miR-302a [263].

The Potential Role of the Exosome Biogenesis Modulation of Ferroptosis-Inhibiting miRNA in Non-Cancer Studies
Several ferroptosis-inhibiting miRNAs, such as miR-19a-3p and miR-424-5p, can regulate exosome-associated non-cancer diseases.For example, shock wave therapy can improve the functions of myocardial ischemia, such as angiogenesis and anti-myocardial fibrosis, by releasing angiogenic exosomal miR-19a-3p [269].Exosomal miR-424-5p from oxygen-glucose-deprivation-activated microglia enhances the injury of brain microvascular endothelial cells and inhibits their vascular formation, which is reversed by miR-424-5p knockdown [271].

Ferroptosis-Modulating miRNAs Are Associated with Some Natural Products
Several natural products (Table 1) and miRNAs (Table 2) exhibiting ferroptosismodulating effects have been individually reported as described above.However, the relationship between these ferroptosis-modulating natural products and miRNAs is rarely investigated.This gap is filled by the literature search using Google Scholar.The results are exemplified in the order of these ferroptosis-inducing (Sections 5.1-5.5) and ferroptosisinhibiting (Section 5.6) miRNAs as follows (Table 4).Finally, the natural-product-centric overview connecting to miRNAs is explored (Section 5.7).
In comparison, the ferroptosis-inhibiting natural product berberine is associated with downregulating ferroptosis-inducing miRNAs (Table 4).miR-429 is highly expressed in colon cancer.Compared to normal tissues, berberine downregulates miR-429 in colon tumors [305].Berberine suppresses the proliferation and migration of endometrial stromal cells by decreasing miR-429 expression, which is reversed by miR-429 overexpression [304].
Ferroptosis-inhibiting natural products, such as berberine and proanthocyanidins, are associated with upregulating ferroptosis-inhibiting miRNAs (Table 4).Berberine raises the level of miR-19a-3p and lowers the level of TF, thus activating MAPK signaling and leading to the apoptosis of cancer cells [308].The ferroptosis inhibitor berberine induces the G2/M arrest and tumor regression of liver cancer cells by upregulating miR-23a-3p, which is reversed by miR-23a-3p inhibition [311].Proanthocyanidins are generally isolated from grape seeds.Grape seed proanthocyanidins suppress azoxymethane-promoted colon tumorigenesis in mice by upregulating miR-19a-3p [292].

Natural-Product-Centric Overview Connecting to Ferroptosis-Modulating miRNAs
Ferroptosis-modulating natural products (Table 1) and miRNAs (Table 2) were independently reported by different studies.Their relationship was summarized in a miRNA-centric manner (Table 4).Alternatively, the natural-product-centric overview to connect with ferroptosis-inducing and ferroptosis-inhibiting miRNAs is summarized (Figure 4).   1 and 2.

Conclusions
Ferroptosis and exosome biogenesis can regulate cell physiological responses in cancer and non-cancer cells.Ferroptosis has the potential to avoid the drug-induced apoptosis resistance of cancer cells [313].Modulating ferroptosis and exosome biogenesis is a Ferroptosis-modulating natural products and miRNAs are mentioned in Tables 1 and 2.

Conclusions
Ferroptosis and exosome biogenesis can regulate cell physiological responses in cancer and non-cancer cells.Ferroptosis has the potential to avoid the drug-induced apoptosis resistance of cancer cells [313].Modulating ferroptosis and exosome biogenesis is a novel strategy for cancer and non-cancer therapies.Natural products are rich resources when applied to cancer and other disease therapies involving the modulation of ferroptosis.Moreover, miRNAs are important in regulating ferroptosis and exosome biogenesis.Therefore, this review proposes a rationale that ferroptosis-modulating natural products may regulate ferroptosis-modulating miRNAs, which in turn control ferroptosis-and exosome-biogenesis-modulating targets.
For the literature search, ferroptosis-modulating natural products (Table 1) and miR-NAs (Table 2) were individually reported.However, there is a knowledge gap with respect to the connection to the modulating effects of the miRNA of natural products acting on ferroptosis.There is another knowledge gap with respect to the limited reports on ferroptosis-and exosome-biogenesis-modulating targets of natural-product-regulated miR-NAs.Those two gaps are innovatively connected in this review, providing a systemic integration for natural-product-modulated miRNAs and their potential targeting for ferroptosis and exosome biogenesis.To fill these gaps, we used literature-search-derived ferroptosis-modulating miRNAs that were added to the miRDB database for identifying the potential targets of ferroptosis-(Table 2) and exosome-biogenesis-modulating genes (Table 3).Moreover, the connection between natural products and miRNAs regarding their ferroptosis induction was organized (Table 4 and Figure 4).
The central concept of this review clearly and innovatively illustrates that ferroptosis modulation may regulate ferroptosis-modulating miRNAs and target their potential genes for regulating ferroptosis and exosome biogenesis in an integrated scope.In other words, ferroptosis-inducing natural products may upregulate ferroptosis-inducing miR-NAs and/or downregulate ferroptosis-inhibiting miRNAs.In turn, they target ferroptosisinhibiting genes and/or ferroptosis-inducing genes.The ferroptosis-inhibiting natural products show the opposite responses.
Notably, this review provides a straightforward literature survey with insufficient evidence of critical assessments for ferroptosis and exosome biogenesis targeting by natural products.Although miRDB is an authoritative and evidence-based miRNA target prediction database, this information may be based on specific cell lines and treatments.It may be differentially expressed or target different cases.When applied to other therapies, a careful assessment of this miRNA targeting information is warranted.Moreover, the connection between natural products and miRNAs is organized by a literature search without validating ferroptosis responses in these reported studies.A detailed assessment of ferroptosis responses, including iron uptake, membrane lipid peroxidation, and ferroptosis signaling, for these natural products and miRNAs is warranted.
Moreover, the ferroptosis-modulating effects of the natural products mentioned in the review are not the sole reason for regulating cancer-and non-cancer-cell responses.Other non-ferroptosis effects are also reported in some of those literature reports.Additionally, this review only focuses on exploring the impact of ferroptosis on exosome biogenesis regarding ferroptosis-modulating natural products and miRNAs, whereas the molecular mechanisms by which exosomes may induce ferroptosis need to be investigated in the future.
Consequently, the connections in the natural product-miRNA-ferroptosis-exosome biogenesis axis are well organized.This review sheds light on the potential directions for integrating miRNAs, exosome biogenesis, and ferroptosis-modulated effects with therapies for cancer and other diseases via natural products.

Table 1 .
Ferroptosis-modulating natural products and their responses to ferroptosis-inducing and ferroptosis-inhibiting genes.

Table 4 .
The connection between ferroptosis-modulating miRNAs and natural products.