Table 2 Treatments targeting STAT/Ferroptosis axis in different diseases

Cucurbitacin B

Triterpenoid Compound

NSCLC

STAT3, GPX4, SLC7A11, COX2, ACSL4

H358, A549, H23, H1650, PC9

Inhibition of STAT3 Activation

In vitro

- CuB Inhibits the Growth of Several NSCLC Cells at Low Doses: CuB showed potent growth inhibition across various NSCLC cell lines with IC50 values ranging from 0.044 to 4.021 µM.

- CuB-Mediated Cytotoxicity is Dependent on Ferroptosis: CuB induced cell death counteracted by ferroptosis inhibitors like DFO, Lip-1, and Fer-1.

- CuB Triggered Ferroptosis in H358 Cells Based on Transcriptomic Analysis: Transcriptomic analysis confirmed CuB’s role in inducing ferroptosis.

- Network Pharmacology Analysis Uncovers Key Genes Implicated in CuB-Induced Ferroptosis in NSCLC: 170 potential targets identified, with STAT3 being a significant target.

- CuB Inhibited STAT3 Activation in H358 Cells: CuB decreased levels of P-STAT3 in a dose-dependent manner, indicating effective targeting of the STAT3 pathway.

- CuB Induced Ferroptosis in H358 Cells Through Targeting of STAT3: Silencing of STAT3 enhanced lipid ROS accumulation and ferroptosis-related proteins. Overexpression of STAT3 alleviated CuB’s ferroptotic effects.

[103]

Baicalein

Flavonoid

Colorectal Cancer

GPX4, ROS, GSH, MDA, Fe2+

HCT116, DLD1, NCM460

JAK2/STAT3

In vivo (CRC xenograft mouse model), In vitro

Ferroptosis in CRC cells: Baicalein induces ferroptosis, characterized by increased ROS, lipid peroxidation, iron accumulation, and mitochondrial damage in CRC cells.

Ferroptosis-dependent effect: Liproxstatin-1 (ferroptosis inhibitor) rescues CRC cells from baicalein-induced death.

JAK2/STAT3/GPX4 Axis: Baicalein inhibits GPX4 expression by blocking JAK2/STAT3 signaling.

Direct Targeting of JAK2: Molecular docking and assays confirm baicalein directly interacts with JAK2.

In vivo Efficacy: Baicalein reduces tumor growth and induces ferroptosis in CRC xenograft models.

[106]

Salidroside

Natural compound (from Rhodiola rosea)

Lung ischemia-reperfusion injury (LIRI)

GPX4, FSP1, SLC1A5, GLS2, ROS, MDA, GSH, Iron

BEAS-2B (human lung epithelial cells)

JAK2/STAT3 signaling

In vivo (mice) & In vitro (BEAS-2B cells)

- Severe ferroptosis occurs in LIRI mice models and H/R-induced BEAS-2B cells.

- Salidroside alleviated ferroptosis, inflammation, and lung injury in LIRI mice.

- Reduced ROS and MDA levels, restored GSH levels, and downregulated pro-ferroptosis molecules (SLC1A5, GLS2).

- Salidroside inhibited the JAK2/STAT3 signaling pathway activation in LIRI.

- STAT3 knockdown enhanced salidroside’s effect in reducing ferroptosis in vitro.

- Salidroside decreased TNF-α and IL-6 levels, mitigating inflammatory responses.

- Reduced lung edema and improved lung function (wet/dry ratio).

[108]

Thiostrepton

Thiopeptide antibiotic

Pancreatic cancer

STAT3, GPX4, ROS, MDA, GSH-PX

Panc-1, MIA PaCa-2, BxPC-3, hTERT-HPNE

STAT3/GPX4 signaling

Both (in vivo mouse model, in vitro pancreatic cancer cells)

TST reduces cell viability and clonogenesis, induces intracellular iron overload, increases ROS and MDA, depletes GSH-PX. TST inhibits STAT3, downregulates GPX4, promoting ferroptosis. In vivo, TST inhibits tumor growth without significant toxicity.

[109]

Paeoniflorin (PF)

Active compound from traditional Chinese medicine

Glioma

NEDD4L, GPX4, Nrf2, STAT3

U251, U87

STAT3/NEDD4L

In vivo (xenograft mouse model), In vitro

Paeoniflorin upregulates NEDD4L, leading to the degradation of STAT3 and the induction of ferroptosis. PF increases ROS levels and reduces cell viability by suppressing Nrf2 and GPX4. PF treatment, combined with RSL3, enhances ferroptosis and tumor suppression.

[110]

Artemisia santolinifolia (AS) + Docetaxel (DTX)

Natural extract + chemotherapeutic

NSCLC

GPX4, ROS

A549, H23

STAT3, Survivin

In vitro (A549, H23)

AS enhanced the cytotoxic effect of DTX via apoptosis in H23 cells (caspase-dependent) and ferroptosis in A549 cells (ROS and GPX4 suppression). STAT3/Survivin signaling was suppressed in both cell lines.

[111]

Bavachin

Flavonoid

Osteosarcoma (OS)

GPX4, ROS, MDA, GSH, SLC7A11, TFRC, DMT1, FTL, FTH

MG63, HOS

STAT3/P53/SLC7A11

In vitro

- Bavachin induces ferroptosis in osteosarcoma cells by increasing intracellular iron and ROS levels.

- Downregulates GPX4, SLC7A11, and inhibits p-STAT3 while upregulating P53.

- Ferroptosis reversed by ferroptosis inhibitors and P53 or STAT3 overexpression.

[112]

Ferulic Acid (FA)

Naturally occurring cinnamic acid derivative (Phenolic compound)

Gamma-radiation-induced liver injury

Upregulated: GPX4, SLC7A11, Nrf2

Downregulated: p-JAK1, p-STAT3

Not applicable (In Vivo Rat Model)

JAK1/STAT3

In Vivo (Rat model)

- Liver Protection: FA significantly inhibited liver damage and restored liver structure and function post-irradiation.

- Enzyme Levels: Reduced serum SGPT and SGOT levels.

- Oxidative Stress: Decreased MDA and ROS; increased GSH

- Iron Metabolism: Lowered ferrous ion (Fe²⁺) content and suppressed iron deposition in liver tissues.

- Signaling Pathways: Inhibited the JAK/STAT pathway (decreased p-JAK1 and p-STAT3) and activated the Nrf2 pathway.

- Ferroptosis Inhibition: Enhanced expression of GPX4 and SLC7A11, preventing ferroptotic cell death.

- Histological Improvements: Reduced inflammatory infiltrates, edema, hepatocyte apoptosis, and iron deposits in liver tissues.

[113]

Jing-Fang n-butanol extract (JFNE) and JFNE-C

Traditional Chinese Medicine extract (n-butanol extract from Nepeta cataria L. and Saposhnikovia divaricata (Trucz.) Schischk.)

Lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages

Upregulated: STAT3, p-STAT3, SLC7A11, GPX4

Downregulated: p53, p-p53

RAW264.7 macrophages

STAT3/p53/SLC7A11

In Vitro (LPS-induced RAW264.7 cell model)

- Anti-Inflammatory: Reduced IL-6, IL-1β, TNF-α levels.

- Antioxidant: Decreased ROS and MDA; increased GSH, GSH-Px, SOD.

- Ferroptosis Inhibition: Lowered Fe²⁺ levels and protected mitochondria.

- Molecular Mechanism: Modulated STAT3/p53/SLC7A11 pathway.

- Active Components: Identified key compounds like Hesperidin and Luteolin in JFNE-C.

- Enhanced Efficacy: JFNE-C showed stronger effects than JFNE.

[114]

Xue-Jie-San (XJS)

Traditional Chinese Herbal Medicine

Crohn’s Disease (CD)

SLC7A11, GPX4, FGL1, NF-κB, STAT3, PTGS2 (COX2), FPN, FTH, FTL

Intestinal epithelial cells (IECs) from rat colitis model

NF-κB, STAT3 pathways

In vivo (TNBS-induced colitis in rat model)

XJS inhibited ferroptosis in IECs by reducing iron overload and lipid peroxidation. It enhanced the SLC7A11/GSH/GPX4 antioxidant system and suppressed the FGL1/NF-κB/STAT3 positive feedback loop, which reduced inflammation and prevented further damage. XJS also upregulated anti-inflammatory cytokines (IL-10) and downregulated pro-inflammatory cytokines (IL-6, IL-17, TNF-α). Histological assessments confirmed reduced inflammation and improved colon structure.

[115]

EGCG

Bioactive compound from green tea

Obesity-exacerbated lung cancer

SLC7A11

A549 (lung cancer), RAW264.7 (macrophages)

STAT1/SLC7A11

In vivo (mice), In vitro (A549)

EGCG inhibits leptin-induced cancer cell proliferation, migration, and invasion. It reverses M2 macrophage polarization and promotes ferroptosis by downregulating STAT1 and SLC7A11 expression. EGCG also modulates gut microbiota, reducing pro-inflammatory bacteria and increasing beneficial microbes, ultimately reducing tumor burden in mice fed a high-fat diet.

[117]

Solamargine (SM)

Glycoalkaloid

Hepatocellular carcinoma

MTCH1, Fe²⁺, MDA, ROS, GSH

HepG2, Huh-7

STAT1/MTCH1

In vivo (mice xenograft), in vitro

SM induces apoptosis and ferroptosis by decreasing MTCH1 expression via the STAT1/MTCH1 axis. Overexpression of STAT1 or MTCH1 reverses the effects of SM in HCC cells and mouse models.

[118]

MaiJiTong (MJT) Granule

Traditional Chinese Medicine

Atherosclerosis

DMT1, SOCS1, p53, SLC7A11, GPX4, ACSL4, LPCAT3, FTH1

RAW264.7 macrophages

STAT6

LDLR−/− mice (in vivo), RAW264.7 cells (in vitro)

MJT attenuates atherosclerosis by inhibiting ferroptosis through STAT6 activation, reducing lipid peroxidation, and improving iron homeostasis by downregulating DMT1/SOCS1.

[119]

Erianin

Natural compound (derived from Dendrobium)

HCC

ROS, Fe²⁺, MDA, GSH, SLC7A11, GPX4

Huh-7, HepG2, L02

JAK2/STAT3 (inactivation)

In vivo (mouse xenograft model) and in vitro (cell culture)

Erianin promotes ferroptosis by increasing ROS, Fe²⁺, and MDA levels while decreasing GSH and ferroptosis-resistance proteins (SLC7A11, GPX4). It suppresses HCC cell proliferation and invasion, and inhibits tumor growth without significant toxicity in mice.

[120]

BEBT-908

Dual PI3K/HDAC Inhibitor

Multiple cancers (hematologic, solid)

p53, SLC7A11, GPX4, Nrf2

Daudi (Burkitt lymphoma), H2122 (NSCLC), HCT116 (colorectal), MC38 (colon adenocarcinoma)

STAT1

Both in vivo (mice) and in vitro

BEBT-908 induces ferroptosis by hyperacetylating p53 and downregulating SLC7A11/GPX4. It enhances MHC I expression and IFNγ signaling, promoting immune cell infiltration and boosting anti-PD1 therapy. Tumor regression and immune memory were observed in vivo models.

[121]

Fer-1

Ferroptosis Inhibitor

ICH

GPx4, ROS

Organotypic hippocampal slices (OHS), mouse ICH model

JAK1/STAT6

Both in vivo (mouse ICH model) and in vitro (OHS)

Fer-1 inhibits neuronal apoptosis by suppressing GPx4 dysfunction and ROS production. It polarizes microglial cells to the M2 phenotype, enhances phagocytic function, alleviates inflammation, improves neurological function, and promotes hematoma absorption after ICH.

[122]

Coumarin-Furoxan Hybrid (Compound 9)

Nitric Oxide (NO) Donor

NSCLC

SLC7A11, GPX4, GSH, MDA

A549, H1975, H1299, H2030

JAK2-STAT3 (Negative Regulation)

In vitro (NSCLC cell lines) and In vivo (H1975 xenograft model)

- Induces apoptosis and ferroptosis via NO release in mitochondria.

- Promotes S-nitrosylation of STAT3, inhibiting its phosphorylation and DNA binding.

- Suppresses JAK2-STAT3 pathway.

- Significantly reduces tumor growth in vivo.

- Decreases GSH, increases MDA, and downregulates ferroptosis-related proteins (SLC7A11, GPX4).

[123]

Polyphyllin VI (PPVI)

Traditional Chinese Medicine

Hepatocellular carcinoma (HCC)

GSH, MDA, Fe2+, GPX4

HCCLM3, Huh7

STAT3/GPX4 (Negative regulation)

In vitro (HCC cell lines) and In vivo (Huh7 xenograft model)

- PPVI induces ferroptosis in HCC cells by reducing GSH, increasing MDA, ROS, and Fe2+.

- PPVI inhibits the invasion and migration of HCC cells through the STAT3/GPX4 axis.

- PPVI blocks STAT3 phosphorylation and decreases GPX4 expression, promoting ferroptosis.

- In vivo, PPVI effectively suppresses tumor growth without notable toxicity.

[125]

Artesunate (ART) + Sorafenib (SOR)

Small-molecule drugs

Non-Hodgkin Lymphoma (NHL)

GPX4, FTH1, GSH, ROS

U2932, SU-DHL4, SU-DHL6 (B-cell lymphoma), Jurkat (T-cell lymphoma), EL4

STAT3 inhibition (p-STAT3 downregulation)

In vitro and In vivo (xenograft mouse model)

ART and SOR synergistically induced ferroptosis and apoptosis via STAT3 inhibition, leading to downregulation of MCL-1 and GPX4, causing cell death, lipid peroxidation, and ROS accumulation. Tumor growth and angiogenesis were significantly suppressed in vivo, showing potential for combination therapy in NHL.

[127]

Propofol

Anesthetic, Antitumor Agent

Gastric Cancer

ROS, Iron, Fe2+, GPX4, SLC7A11, MDA, GSH

SGC7901, BGC823

STAT3 inhibition (via miR-125b-5p)

In vitro (cell lines) and In vivo (xenograft in nude mice)

Propofol induces ferroptosis and inhibits malignant phenotypes (proliferation, invasion, migration) of gastric cancer cells by upregulating miR-125b-5p, which targets STAT3. Increased ROS, iron, Fe2 + levels, and decreased GPX4, SLC7A11, and GSH were observed. Tumor growth was suppressed in vivo.

[128]

Propofol

Anesthetic

Colorectal Cancer (CRC)

STAT3, CHAC1, PTGS2, GPX4, ROS, Fe2+, GSH

SW480 (CRC), NCM460 (normal colonic cells)

Downregulates STAT3 expression

In vitro

Propofol induced ferroptosis in CRC cells by downregulating STAT3. It increased cellular iron, ROS, and Fe2 + levels, while promoting the expression of CHAC1 and PTGS2 and inhibiting GPX4. Overexpression of STAT3 reversed these effects.

[129]

Dimethyl Fumarate (DMF)

FDA-approved drug

DLBCL (Diffuse Large B-cell Lymphoma)

GPX4, GSH, 5-lipoxygenase (5-LOX), FSP1

GCB DLBCL, ABC DLBCL, SU-DHL-6, DOHH2, OCI-Ly10

NF-κB/STAT3 pathways

In vitro, In vivo (Zebrafish, Mouse models)

DMF induces ferroptosis in GCB DLBCL by depleting GSH and inhibiting GPX4, increasing lipid peroxidation. In ABC DLBCL, DMF impairs NF-κB and STAT3 signaling by succinating IKK2 and JAK1. Synergistic effects seen when combined with FSP1 and BCL-2 inhibitors. Significant tumor reduction observed in xenograft models.

[130]

Metformin + Sorafenib

Antidiabetic + Anticancer

HCC

GPX4 (downregulated), ACSL4 (upregulated), ROS, Fe²⁺

Huh7, Hep3B (and sorafenib-resistant versions Huh7/SR, Hep3B/SR)

ATF4/STAT3, p-STAT3, p-STAT1

Both in vitro (cell lines) and in vivo (mouse model)

Metformin promotes ferroptosis by increasing ROS, lipid peroxidation, and Fe²⁺ accumulation. Downregulating ATF4 inhibits STAT3 activity, enhancing sensitivity to sorafenib. Reverses drug resistance.

[132]

Artesunate

Antimalarial/Anticancer

Diffuse Large B Cell Lymphoma (DLBCL)

GPX4 (downregulated), FTH1 (downregulated), ROS, MDA

U2932, SU-DHL2, SU-DHL4, SU-DHL6

STAT3, p-STAT3

Both in vitro (cell lines) and in vivo (xenograft mouse model)

ART induces apoptosis, autophagy, and ferroptosis in DLBCL cells. Inhibits STAT3 signaling, reducing proliferation. Knockdown of STAT3 enhances ART-induced autophagy, ferroptosis, and apoptosis. Validated in vivo using a xenograft model.

[133]

Auranofin (AUR)

FDA-approved anti-rheumatoid arthritis (anti-RA) drug

Hereditary hemochromatosis, hepcidin-deficiency related disorders

TXNRD (Thioredoxin Reductase), GPX4, SLC7A11, P53, STAT3, IL-6, NF-κB, ROS, MDA, GSH

Huh7 cells, C57BL/6J mice, Hfe⁻/⁻ mice

NF-κB/IL-6/STAT3 and BMP/SMAD pathways

In vitro (Huh7 cells) and In vivo (C57BL/6J and Hfe⁻/⁻ mice)

- Hepcidin Upregulation: Auranofin (AUR) upregulated hepcidin via NF-κB/IL-6/STAT3 signaling.

- Iron Overload Reduction: In male Hfe⁻/⁻ mice, AUR reduced systemic iron overload.

- Ferroptosis Induction: High-dose AUR induced ferroptosis, characterized by lipid peroxidation and ROS accumulation.

- Sex-Specific Effects: Estrogen reduced AUR effectiveness in female mice.

- Toxicity: High-dose AUR caused 100% mortality through ferroptosis in mice, but this was mitigated by ferroptosis inhibitor (Fer-1).