Silymarin (Milk Thistle) silibinin / NRF2 Cancer Research Results

SIL, Silymarin (Milk Thistle) silibinin: Click to Expand ⟱

Features:

Silymarin (Milk Thistle) Flowering herb related to daisy and ragweed family.
Silibinin (INN), also known as silybin is the major active constituent of silymarin, a standardized extract of the milk thistle seeds.
-a flavonoid combination of 65–80% of seven flavolignans; the most important of these include silybin, isosilybin, silychristin, isosilychristin, and silydianin. Silybin is the most abundant compound in around 50–70% in isoforms silybin A and silybin B

-Note half-life 6hrs?.
BioAv not soluble in water, low bioAv (1%). 240mg yielded only 0.34ug/ml plasma level. oral administration of SM (equivalent to 120 mg silibinin), total (unconjugated + conjugated) silibinin concentration in plasma was 1.1–1.3 μg/mL, so can not achieve levels used in most in-vitro studies.
Pathways:
- results for both inducing and reducing ROS in cancer cells. In normal cell seems to consistently lower ROS. Reports show both ROS↑ and ROS↓ in cancer models; systemic pro-oxidant effects may require higher exposures than typical oral dosing, but local or combination contexts may differ. (level in GUT could be much higher (800uM).
- ROS↑ related: MMP↓(ΔΨm), Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑,
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑">NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓(context-dependent; often stress-activated), Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, uPA↓, VEGF↓, FAK↓, NF-κB↓, CXCR4↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, DNMTs↓, P53↑, HSP↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, FAK↓, ERK↓, EMT↓,
- inhibits glycolysis and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, GRP78↑(ER stress), Glucose↓, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, PDGF↓, EGFR↓,
- inhibits Cancer Stem Cells : CSC↓, Hh↓, GLi1↓, β-catenin↓, Notch2↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK, - SREBP (related to cholesterol).
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells

Rank	Pathway / Axis	Cancer Cells	Normal Cells	TSF	Primary Effect	Notes / Interpretation
1	ROS / redox buffering + mitochondrial protection	Often ↑ stress susceptibility; can support apoptosis when survival signaling is blocked	↓ oxidative stress; mitochondrial protection	P, R, G	Context-selective redox modulation	Silymarin is classically cytoprotective/antioxidant in normal tissues (notably liver), while in tumors it can weaken pro-survival adaptation and increase vulnerability to stressors and therapy.
2	Intrinsic apoptosis (mitochondria → caspases)	↑ apoptosis signaling; ↑ caspase activation	↔ minimal activation	G	Cell death execution	Common downstream outcome in cancer models: apoptosis increases after earlier signaling/redox shifts and/or checkpoint disruption.
3	Cell-cycle control (cyclins/CDKs; checkpoints)	↑ arrest (G1/S or G2/M depending on model)	↔	G	Cytostasis	Typically observed as reduced proliferation with checkpoint engagement; timing usually later than kinase phosphorylation changes.
4	NF-κB inflammatory transcription	↓ NF-κB activity; ↓ inflammatory/pro-survival tone	↔ or protective anti-inflammatory effect	R, G	Anti-inflammatory / anti-survival transcription	NF-κB suppression can reduce tumor-promoting inflammation and blunt stress-adaptive survival programs.
5	JAK/STAT3 axis (incl. PD-L1 / immune escape programs in some models)	↓ STAT3 signaling (context); may ↓ PD-L1 in certain tumor contexts	↔	R, G	Reduced survival + immune-evasion signaling	Reported to attenuate STAT3-driven tumor programs and, in some contexts, reduce immune-suppressive signaling (model dependent).
6	PI3K → AKT → mTOR survival / growth signaling	↓ PI3K/AKT/mTOR signaling (context)	↔	R, G	Growth/survival suppression	Reduced PI3K/AKT/mTOR tone increases sensitivity to apoptosis and can reinforce cell-cycle arrest.
7	MAPK re-wiring (ERK/p38/JNK balance)	Stress-MAPK shifts; ERK tone often reduced or re-patterned	↔	P, R, G	Signal reprogramming	Early phosphorylation shifts can precede later gene-expression changes; exact ERK direction is model and dose dependent.
8	Angiogenesis (VEGF and angiogenic factors)	↓ VEGF / angiogenesis outputs	↔	G	Anti-angiogenic support	Typically reflected in reduced pro-angiogenic expression/secretion and angiogenesis-related phenotypes over longer windows.
9	EMT / invasion / migration programs (incl. TGF-β/Smad-associated EMT in some systems)	↓ EMT markers; ↓ migration/invasion	↔	G	Anti-invasive phenotype	Often presents as restoration of epithelial markers and suppression of migration/invasion assays; commonly a later phenotype-level outcome.
10	Xenobiotic handling (Phase I/II enzymes; cytoprotection / chemoprevention framing)	May alter carcinogen activation/detox balance	↑ detox / cytoprotection against xenobiotics	G	Chemopreventive protection	A key “dual strategy” theme: protection of normal tissue from toxins/therapy while modulating tumor response pathways.
11	Drug resistance / efflux (MDR phenotype; P-gp-related resistance in some models)	May ↓ functional MDR and ↑ chemo sensitivity (context)	↔	R, G	Chemo-sensitization support	Reported synergy with chemotherapy in resistant tumor settings; transporter direction can be context-specific, so present as “reported to reduce functional resistance” rather than a universal single-transporter claim.
12	Immune microenvironment signaling (cytokines / macrophage recruitment in some models)	May ↓ pro-tumor cytokine programs and recruitment signals (context)	↔	G	Anti-inflammatory tumor microenvironment shift	Immune-modulatory effects are increasingly discussed, but they are more model-dependent and typically show on longer time scales.

Time-Scale Flag (TSF): P / R / G

P: 0–30 min (primary/physical–chemical effects; rapid signaling / phosphorylation shifts)
R: 30 min–3 hr (redox signaling + acute stress-response signaling)
G: >3 hr (gene-regulatory adaptation and phenotype-level outcomes)

NRF2, nuclear factor erythroid 2-related factor 2: Click to Expand ⟱

Source: TCGA

Type: Antiapoptotic

Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response.
-One way to estimate Nrf2 induction is through the expression of NQO1.
NQO1, the most potent inducer:
SFN 0.2 μM,
quercetin (2.5 μM),
curcumin (2.7 μM),
Silymarin (3.6 μM),
tamoxifen (5.9 μM),
genistein (6.2 μM ),
beta-carotene (7.2μM),
lutein (17 μM),
resveratrol (21 μM),
indol-3-carbinol (50 μM),
chlorophyll (250 μM),
alpha-cryptoxanthin (1.8 mM),
and zeaxanthin (2.2 mM)

1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects.
2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death.
3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress

-In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies.
-Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate.
Decreased Nrf2 expression: Skine, Liver, Pancreatic.
-Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer
- "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1.

Nrf2 Inhibitors and Activators
Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin
Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api
- potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany

Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue.
– In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis.
– In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity.
– This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming.
– Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies.
– High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types.
– While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression.

NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS).
-Brusatol: most cited natural inhibitors of Nrf2.
-Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent.
-Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent .
-Oridonin:
-Wogonin: although its effects might be cell‑ and dose‑specific.
- Withaferin A

Scientific Papers found: Click to Expand⟱

3324-

SIL,

Silymarin prevents NLRP3 inflammasome activation and protects against intracerebral hemorrhage

*ROS↓, *TAC↑, *NF-kB↓, *IL2↓, *NRF2↑, *HO-1↑, *neuroP↑, *Inflam↓, *NLRP3↓,

3319-

SIL,

Silymarin and neurodegenerative diseases: Therapeutic potential and basic molecular mechanisms

Review,

AD,

Review,

Park,

Review,

Stroke,

*neuroP↑, *ROS↓, *Inflam↓, *Apoptosis↓, *BBB?, *tau↓, *NF-kB↓, *IL1β↓, *TNF-α↓, *IL4↓, *MAPK↓, *memory↑, *cognitive↑, *Aβ↓, *ROS↓, *lipid-P↓, *GSH↑, *MDA↓, *SOD↑, *Catalase↑, *AChE↓, *BChE↓, *p‑ERK↓, *p‑JNK↓, *p‑p38↓, *GutMicro↑, *COX2↓, *iNOS↓, *TLR4↓, *neuroP↑, *Strength↑, *AMPK↑, *MMP↑, *necrosis↓, *NRF2↑, *HO-1↑,

3318-

SIL,

Pharmaceutical prospects of Silymarin for the treatment of neurological patients: an updated insight

Review,

AD,

Review,

Park,

*hepatoP↑, *neuroP↑, *TLR4↓, *TNF-α↓, *IL1β↓, *NF-kB↓, *memory↑, *cognitive↑, *NRF2↑, *HO-1↑, *ROS↓, *Akt↑, *mTOR↑, *SOD↑, *Catalase↑, *GSH↑, *IL10↑, *IL6↑, *NO↓, *MDA↓, *AChE↓, *MAPK↓, *BDNF↑,

3316-

SIL,

Chemo,

Silymarin Nanoparticles Counteract Cognitive Impairment Induced by Doxorubicin and Cyclophosphamide in Rats; Insights into Mitochondrial Dysfunction and Nrf2/HO-1 Axis

Inflam↓, antiOx↓, neuroP↑, cognitive↑, NRF2↑, HO-1↑, memory↑, AChE↓, Casp3↓,

3315-

SIL,

Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats

in-vivo,

Nor,

rats

neuroP↑, *NRF2↑, *HO-1↑, *lipid-P↓, *GSH↑, *SOD↑, *Catalase↑, *GPx↑, *NF-kB↓, *TNF-α↓, *JNK↓, *Bcl-2↑, *BAX↑,

3313-

SIL,

Silymarin attenuates post-weaning bisphenol A-induced renal injury by suppressing ferroptosis and amyloidosis through Kim-1/Nrf2/HO-1 signaling modulation in male Wistar rats

in-vivo,

NA,

50-100 mg/kg/day

Twenty-four male Wistar rats

*NRF2↑, *HO-1↑, *creat↓, *BUN↓, *RenoP↑, *MDA↓, *TNF-α↓, *IL1β↓, *Cyt‑c↓, *Casp3↓, *GSTs↓, *GSH↑, *GPx4↑, *SOD↑, *GSR↓, *Ferroptosis↓,

3312-

SIL,

Silymarin Alleviates Oxidative Stress and Inflammation Induced by UV and Air Pollution in Human Epidermis and Activates β-Endorphin Release through Cannabinoid Receptor Type 2

Human,

Nor,

skin

*antiOx↑, *Inflam↓, *ROS↓, *IL1α↓, *AhR↑, *NRF2↑, *IL8↓,

3311-

SIL,

Silymarin protects against acrylamide-induced neurotoxicity via Nrf2 signalling in PC12 cells

in-vitro,

Nor,

PC12

*antiOx↑, *Inflam↓, AntiCan↑, *ROS↓, *MDA↓, *GSH↓, *NRF2↑, *GPx↑, *GCLC↑, *GCLM↑,

3310-

SIL,

Silymarin attenuates paraquat-induced lung injury via Nrf2-mediated pathway in vivo and in vitro

in-vitro,

Lung,

A549

Inflam↓, MPO↓, NO↓, iNOS↓, ROS↓, MDA↑, SOD↑, Catalase↑, GPx↑, NRF2↑, HO-1↑, NADPH↑,

3309-

SIL,

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

Review,

NA,

*ROS↓, *IronCh↑, *MMP↑, *NRF2↑, *Inflam↓, *hepatoP↑, *HSPs↑, *Trx↑, *SIRT2↑, *GSH↑, *ROS↑, *NADPH↓, *iNOS↓, *NF-kB↓, *BioAv↓, *Dose↝, *BioAv↑,

3308-

SIL,

Structural basis of Nrf2 activation by flavonolignans from silymarin

Analysis,

NA,

*antiOx↑, *chemoP↑, *NRF2↑,

3307-

SIL,

Flavolignans from Silymarin as Nrf2 Bioactivators and Their Therapeutic Applications

Review,

Var,

*NRF2↑, *antiOx↑, *chemoP↑, *Inflam↓, *BioAv↑, eff↑, *NQO1↑, TNF-α↓, IL6↓, *GSH↑, *ROS↓, *MDA↓, eff↑, *hepatoP↑, *GPx↑, *SOD↑, *Catalase↑, *HO-1↑, *neuroP↑,

3302-

SIL,

Protective effects of silymarin in glioblastoma cancer cells through redox system regulation

in-vitro,

GBM,

U87MG

264.6 μM

NRF2↑, HO-1↑, Trx↑, antiOx↑,

Showing Research Papers: 1 to 13 of 13

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 13

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↑, 4, Catalase↑, 4, Ferroptosis↓, 1, GCLC↑, 1, GCLM↑, 1, GPx↑, 3, GPx4↑, 1, GSH↓, 1, GSH↑, 6, GSR↓, 1, GSTs↓, 1, HO-1↑, 6, lipid-P↓, 2, MDA↓, 5, NQO1↑, 1, NRF2↑, 10, ROS↓, 8, ROS↑, 1, SOD↑, 5, TAC↑, 1, Trx↑, 1,

Metal & Cofactor Biology ⓘ

IronCh↑, 1,

Mitochondria & Bioenergetics ⓘ

MMP↑, 2,

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1, BUN↓, 1, NADPH↓, 1, SIRT2↑, 1,

Cell Death ⓘ

AhR↑, 1, Akt↑, 1, Apoptosis↓, 1, BAX↑, 1, Bcl-2↑, 1, Casp3↓, 1, Cyt‑c↓, 1, Ferroptosis↓, 1, iNOS↓, 2, JNK↓, 1, p‑JNK↓, 1, MAPK↓, 2, necrosis↓, 1, p‑p38↓, 1,

Protein Folding & ER Stress ⓘ

HSPs↑, 1,

Proliferation, Differentiation & Cell State ⓘ

p‑ERK↓, 1, mTOR↑, 1,

Angiogenesis & Vasculature ⓘ

NO↓, 1,

Barriers & Transport ⓘ

BBB?, 1,

Immune & Inflammatory Signaling ⓘ

COX2↓, 1, IL10↑, 1, IL1α↓, 1, IL1β↓, 3, IL2↓, 1, IL4↓, 1, IL6↑, 1, IL8↓, 1, Inflam↓, 6, NF-kB↓, 5, TLR4↓, 2, TNF-α↓, 4,

Synaptic & Neurotransmission ⓘ

AChE↓, 2, BChE↓, 1, BDNF↑, 1, tau↓, 1,

Protein Aggregation ⓘ

Aβ↓, 1, NLRP3↓, 1,

Drug Metabolism & Resistance ⓘ

BioAv↓, 1, BioAv↑, 2, Dose↝, 1,

Clinical Biomarkers ⓘ

creat↓, 1, GutMicro↑, 1, IL6↑, 1,

Functional Outcomes ⓘ

chemoP↑, 2, cognitive↑, 2, hepatoP↑, 3, memory↑, 2, neuroP↑, 5, RenoP↑, 1, Strength↑, 1,
Total Targets: 77

Scientific Paper Hit Count for: NRF2, nuclear factor erythroid 2-related factor 2

13 Silymarin (Milk Thistle) silibinin
1 Chemotherapy

Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:154  Target#:226  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

Silymarin (Milk Thistle) silibinin / NRF2 Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Synaptic & Neurotransmission ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Metal & Cofactor Biology ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Protein Folding & ER Stress ⓘ

Proliferation, Differentiation & Cell State ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Synaptic & Neurotransmission ⓘ

Protein Aggregation ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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