Juglone / LC3I Cancer Research Results

JG, Juglone: Click to Expand ⟱
Features:
Found in roots, leaves, nut-hulls, bark and wood of walnut trees.
Juglone (5-hydroxy-1,4-naphthoquinone)
Juglans nigra refers to the black walnut tree, which is one of the most well-known sources of juglone
-Research has focused on the hulls (the green outer covering of the walnut) because they have the highest concentrations.
-Fresh hulls can contain juglone levels in the range of approximately 1–5% of the dry weight

-Juglone can redox cycle to generate reactive oxygen species (ROS).
-Increasing Bax, decreasing Bcl‑2, caspase activation, and MMP depolarization.
-Modulation of MAPK pathways (including ERK, JNK, and p38)
-May inhibit NF‑κB signaling
-Cause DNA damage or stress that, in turn, leads to p53 pathway activation— Pin1 Inhibition
–Pin1, a peptidyl-prolyl cis/trans isomerase, is frequently overexpressed in cancer.

-ic50 maybe 5-10uM
-For matching 5uM, crude estimate is 5mg consumption of juglone required which might be 1.5 g of black walnut hull material

Juglone — Juglone (5-hydroxy-1,4-naphthoquinone; JG) is a naturally occurring redox-active naphthoquinone found in plants of the Juglans genus, including black walnut (Juglans nigra), with particularly high concentrations reported in green walnut hulls. It is best classified as a natural small-molecule quinone and experimental anticancer agent rather than an established therapeutic drug. Its anticancer activity is strongly concentration-dependent and reflects electrophilic thiol reactivity, redox cycling, oxidative stress, mitochondrial injury, ferroptosis, apoptosis, and modulation of several oncogenic signaling pathways. Juglone is also widely used experimentally as a Pin1 inhibitor, although this designation should not imply high target selectivity because juglone can covalently modify protein sulfhydryl groups and affect transcription and other cellular proteins.

Primary mechanisms (ranked):

  1. Quinone redox cycling and electrophilic thiol reactivity causing ↑ ROS, ↓ glutathione-dependent antioxidant capacity, oxidative macromolecular injury, and oxidative-stress-driven cell death.
  2. Ferroptosis induction through lipid peroxidation and disruption of antioxidant defenses, including ↓ GPX4 and, in some cancer models, ↓ NRF2 signaling or activation of the FOSL1-HMOX1 axis.
  3. Mitochondrial apoptosis through ↓ mitochondrial membrane potential, ↑ Bax/Bcl-2 ratio, cytochrome-c release, and caspase activation.
  4. Pin1 inhibition contributing to suppression of proliferation, cancer-cell stemness, EMT, migration, angiogenesis, and oncogenic signaling; however, juglone is not a highly selective Pin1 pharmacological probe.
  5. Suppression of PI3K-AKT and related survival signaling, frequently downstream of or amplified by oxidative stress.
  6. Cell-cycle arrest through modulation of cyclins, CDKs, p21, p27, p53, and related checkpoint pathways.
  7. Stress-MAPK modulation, particularly ↑ p38 and ↑ JNK, contributing to apoptosis, ferroptosis, and autophagic responses.
  8. Suppression of EMT, invasion, stem-like phenotype, Wnt/β-catenin signaling, HIF-1α, VEGF, and angiogenic/metastatic programs in selected cancer models.
  9. Autophagy induction as a context-dependent stress response that can interact with apoptosis and oxidative injury.

Bioavailability / PK relevance: Free juglone has unfavorable drug-delivery characteristics, including hydrophobicity, high chemical reactivity, rapid disposition, and substantial renal exposure. In an animal intravenous PK study, free juglone had a plasma half-life of approximately 2 hours and showed prominent kidney localization; sterically stabilized liposomal delivery increased plasma half-life approximately 12-fold, improved tumor localization, and reduced renal toxicity. Robust human oral pharmacokinetic data are lacking. Consequently, dietary or walnut-hull intake cannot presently be converted reliably into a systemic micromolar juglone exposure.

In-vitro vs systemic exposure relevance: Most direct anticancer studies use approximately low-to-tens-of-micromolar juglone, commonly around 5–20 µM. Whether these free-drug concentrations can be maintained safely in human tumors is not established. Recent quantitative work also demonstrates limited intracellular accumulation despite extracellular juglone exposure. Thus, common in-vitro concentrations should not be assumed to be achievable through oral walnut or black-walnut-hull consumption.

Clinical evidence status: Preclinical. Juglone has substantial cell-culture evidence and multiple mouse/xenograft studies showing antitumor activity, including apoptosis, ferroptosis, anti-metastatic, and anti-angiogenic effects. There is no established anticancer dose, regulatory approval, or convincing human clinical efficacy evidence for juglone itself. Translation is limited by nonspecific electrophilic/redox chemistry, systemic toxicity risk, formulation and pharmacokinetic limitations, and the uncertain therapeutic window between cancer and normal tissues.

Juglone Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Quinone redox cycling and thiol reactivity ↑ ROS; ↑ oxidative stress; ↓ cellular thiol buffering ↑ oxidative injury possible P/R Oxidative-stress overload Central upstream mechanism. Juglone participates in redox cycling and can react with protein and glutathione sulfhydryl groups; this contributes to efficacy but also limits selectivity.
2 Glutathione and antioxidant defense ↓ GSH; ↓ GPX4; ↓ SOD (model-dependent) ↓ antioxidant reserve possible (dose-dependent) R Loss of redox buffering Creates a permissive environment for ROS accumulation, lipid oxidation, apoptosis, and ferroptosis.
3 Ferroptosis and lipid peroxidation ↑ ferroptosis; ↑ lipid peroxidation; ↑ MDA; ↑ labile iron Potential ferroptotic toxicity at sufficient exposure R/G Iron-dependent oxidative cell death Strong recent evidence in hepatocellular carcinoma and glioblastoma; pathway execution is cancer-type dependent.
4 NRF2 GPX4 antioxidant axis ↓ NRF2; ↓ GPX4 (model-dependent) Not established R/G Ferroptosis sensitization Demonstrated particularly in glioblastoma. NRF2 modulation should not be generalized to every tumor model.
5 FOSL1 HMOX1 ferroptosis axis ↑ FOSL1; ↑ HMOX1 Not established G Ferroptosis amplification Recent HCC and pan-cancer evidence identifies this transcriptional axis as an important juglone-responsive ferroptotic mechanism.
6 Mitochondrial membrane integrity ↓ membrane potential; ↑ cytochrome-c release Mitochondrial toxicity possible R Intrinsic apoptosis initiation Observed across breast, gastric, prostate, and other cancer models.
7 BAX BCL2 caspase apoptosis ↑ BAX; ↓ BCL2; ↑ caspase-3/7; ↑ caspase-8/9 Apoptosis possible at cytotoxic exposure R/G Programmed cell death Both intrinsic and extrinsic apoptotic pathways can participate. Recent colorectal cancer data support activation of caspase-8 as well as mitochondrial caspase-9 signaling.
8 Pin1 prolyl isomerase ↓ Pin1 activity/function ↓ Pin1 and other thiol-sensitive proteins possible P/R Reduced oncogenic signaling and stemness Important experimental target associated with ↓ proliferation, ↓ EMT, ↓ stemness, and ↓ angiogenesis. Juglone is not Pin1-selective and can directly modify sulfhydryl-containing proteins.
9 PI3K AKT survival signaling ↓ PI3K; ↓ AKT; ↓ p-AKT Context-dependent R/G Survival pathway suppression ROS scavenging can partially reverse this effect in NSCLC, indicating substantial coupling between oxidative stress and PI3K-AKT inhibition.
10 p38 JNK stress signaling ↑ p38; ↑ JNK Context-dependent R Stress-mediated apoptosis and ferroptosis Activation is frequently associated with ROS production and can contribute to NRF2-GPX4 suppression and programmed cell death.
11 Cell cycle checkpoints ↑ arrest; ↓ CDK2; ↓ CDK4; ↓ cyclins; ↑ p21; ↑ p27 Growth inhibition possible G Proliferation blockade Cell-cycle phase varies by model. Recent colorectal cancer data support G0/G1 arrest with suppression of CCND1, CCNB1, CDK2, and CDK4.
12 p53 DNA damage response ↑ DNA damage; ↑ γH2AX; ↑ p53 (model-dependent) Genotoxicity possible R/G Checkpoint activation and apoptosis May arise partly from quinone-driven ROS and electrophilic stress rather than a specific DNA-targeting interaction.
13 Intracellular calcium and mitochondrial stress ↑ Ca²⁺ (model-dependent) Not established P/R Apoptotic signaling Increased intracellular Ca²⁺ has been demonstrated in MCF-7 cells together with ROS elevation and mitochondrial depolarization.
14 EMT migration and invasion ↓ EMT; ↑ E-cadherin; ↓ N-cadherin; ↓ Snail; ↓ migration; ↓ invasion Not established G Reduced metastatic phenotype Pin1, AKT-GSK3β-Snail, TGF-β-related, and other signaling systems have been implicated depending on tumor model.
15 Cancer stemness ↓ sphere formation; ↓ tumor-initiating phenotype Not established G Reduced self-renewal and metastatic potential Pin1 inhibition appears to contribute. Effects have been demonstrated in colorectal and other tumor-initiating cell models.
16 Wnt beta-catenin signaling ↓ Wnt/β-catenin (model-dependent) Not established G Reduced invasion and angiogenesis Most clearly demonstrated in pancreatic cancer models; not necessarily a universal primary mechanism.
17 HIF-1α VEGF angiogenic signaling ↓ HIF-1α; ↓ VEGF; ↓ angiogenesis Potential vascular effects not well characterized G Reduced tumor vascular support Secondary/contextual anticancer mechanism reported in pancreatic cancer and Pin1-related models.
18 Autophagy stress response ↑ LC3-II; ↑ Beclin-1; ↓ p62 (model-dependent) Context-dependent G Autophagic stress and death crosstalk Autophagy can accompany ROS/MAPK signaling but its contribution to net cytotoxicity varies by cell type and experimental conditions.
19 Chemosensitization ↑ drug cytotoxicity in selected combinations Potential ↑ combination toxicity G Combination-treatment sensitization Juglone can enhance etoposide cytotoxicity through Pin1-related mechanisms, but sequence of administration can substantially alter the interaction.
20 Clinical Translation Constraint Effective concentrations commonly ~5–20 µM in vitro Systemic electrophilic and oxidative toxicity limits selectivity G Uncertain therapeutic window Human bioavailability and therapeutic exposure are not established. Free juglone has short animal plasma persistence, renal accumulation, and nephrotoxicity; formulations such as liposomes materially alter PK and distribution.

P: 0–30 min     R: 30 min–3 hr     G: >3 hr

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LC3I, Lysosomal-associated membrane protein 2A: Click to Expand ⟱
Source:
Type:
LC3I (Lysosomal-associated membrane protein 2A, also known as LAMP2A) is a protein that plays a crucial role in the process of chaperone-mediated autophagy (CMA). CMA is a type of autophagy, a cellular process in which cells recycle and remove damaged or dysfunctional components.
LC3I is overexpressed in certain types of cancer, including breast, lung, and colon cancer.
The conversion of LC3-I to LC3-II (the lipidated form) is a key step in autophagy activation.

: In many cancers, low levels of LC3-I may indicate impaired autophagy, which can lead to the accumulation of damaged proteins and organelles, contributing to tumorigenesis. This is often associated with poor prognosis.
Tumor Promoting Role: In some contexts, the presence of LC3-I may indicate a baseline level of autophagy that is necessary for cellular homeostasis, but its role is less prominent compared to LC3-II.
Generally, decreased expression of LC3-I is associated with worse prognosis in many cancers, indicating its potential role in tumor suppression through the regulation of autophagy. However, the context-dependent nature of LC3-I's function suggests that further research is needed to fully understand its roles in different cancer types and its potential as a therapeutic target.


Scientific Papers found: Click to Expand⟱
1917- JG,    Inhibition of human leukemia cells growth by juglone is mediated via autophagy induction, endogenous ROS production, and inhibition of cell migration and invasion
- in-vitro, AML, HL-60
selectivity↑, LC3I↑, LC3II↑, Beclin-1/ATG6↑, ROS↑, tumCV↓, Dose↝, TumAuto↑,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↑, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

tumCV↓, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

Beclin-1/ATG6↑, 1,   LC3I↑, 1,   LC3II↑, 1,   TumAuto↑, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

Dose↝, 1,   selectivity↑, 1,  
Total Targets: 8

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: LC3I, Lysosomal-associated membrane protein 2A
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#:105  Target#:720  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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