Isoliquiritigenin / SREBP1/SREBF1 Cancer Research Results

ISL, Isoliquiritigenin: Click to Expand ⟱
Features:

ISL is a distinct natural chalcone, chemically identified as 2′,4′,4-trihydroxychalcone, found particularly in licorice species such as Glycyrrhiza spp.ISL has substantial preclinical evidence involving anticancer, anti-inflammatory, antioxidant, metabolic, and neuroprotective effects. Reported anticancer actions include inhibition of proliferation, angiogenesis, EMT, invasion, and metastasis, with induction of apoptosis, cell-cycle arrest, autophagy, or ferroptosis depending on the model. Frequently reported pathways include PI3K/AKT/mTOR, NF-κB, STAT3, MAPK, Wnt/β-catenin, Nrf2, and Src signalling.

Isoliquiritigenin — isoliquiritigenin (ISL; 2′,4′,4-trihydroxychalcone) is a naturally occurring polyphenolic chalcone found particularly in licorice roots from Glycyrrhiza species. It is formally classified as a flavonoid-family chalcone rather than an isoflavone. ISL is a pleiotropic experimental bioactive compound with anticancer, anti-inflammatory, metabolic, antioxidant/pro-oxidant, and neuroprotective activities. Anticancer effects are strongly model- and concentration-dependent, and clinically relevant systemic exposure to unconjugated ISL is substantially more limited than the micromolar concentrations commonly used in cell culture. ISL also has weak phytoestrogenic activity and can interact with estrogen receptors.

Primary mechanisms (ranked):

  1. Suppression of PI3K/AKT/mTOR survival and growth signalling, with associated apoptosis, autophagy, cell-cycle arrest, and inhibition of metabolic reprogramming.
  2. Mitochondrial apoptosis through ↑ Bax/Bcl-2 ratio, mitochondrial dysfunction, cytochrome-c release, and caspase activation.
  3. Suppression of JAK/STAT signalling, particularly JAK2/STAT3, reducing survival, proliferation, inflammatory signalling, and treatment resistance.
  4. ROS-dependent cytotoxic signalling in several cancer models, including ROS-mediated inhibition of p38/mTOR/STAT3 and activation of mitochondrial apoptosis.
  5. Suppression of NF-κB-mediated inflammatory and prosurvival signalling.
  6. Inhibition of EMT, invasion, and metastasis through pathways including PI3K/AKT, β-catenin, MMPs, Snail-family transcription factors, and restoration of E-cadherin.
  7. Suppression of tumor lipid synthesis and metabolic adaptation through AMPK activation with inhibition of SREBF1/FASN and, in colorectal cancer, FGFR4-associated lipid metabolism.
  8. Modulation of arachidonic-acid/eicosanoid signalling, including inhibition of COX-2, mPGES-1, and CYP4A11 in selected tumor models.
  9. NRF2 modulation is context-dependent: NRF2 activation can provide antioxidant and anti-inflammatory protection in non-malignant/neural models, whereas suppression of NRF2 antioxidant defence has been reported as a mechanism of radiosensitization in some cancer models.
  10. Weak estrogen-receptor agonist/SERM-like activity; low concentrations may stimulate ER-responsive cells under some conditions, making this a relevant mechanistic and safety consideration rather than a uniformly anticancer effect.

Bioavailability / PK relevance: Oral ISL undergoes substantial intestinal absorption barriers and rapid phase-II metabolism, particularly glucuronidation. Animal studies report oral bioavailability of roughly 20–34%, but circulating parent ISL is transient and extensively converted to conjugated metabolites. Human pharmacokinetic studies of licorice-containing Kampo preparations confirm detectable ISL exposure but at levels substantially below many experimental cancer-cell concentrations. Low aqueous solubility and rapid metabolism have driven development of nanoparticles, micelles, SMEDDS, and structural derivatives to improve exposure.

In-vitro vs systemic exposure relevance: Many anticancer experiments use approximately 10–100+ µM ISL, whereas parent-compound concentrations achieved after conventional oral botanical exposure are generally much lower because of rapid intestinal glucuronidation and systemic metabolism. Consequently, direct translation of high-micromolar in-vitro cytotoxicity to oral supplementation is poor. Some lower-concentration receptor, enzyme, inflammatory, and metabolic effects may be more pharmacologically plausible.

Clinical evidence status: Preclinical. Extensive cell-culture and multiple animal xenograft studies support anticancer activity, but ISL itself is not an established cancer treatment and there is no convincing randomized human anticancer efficacy evidence. Human studies primarily provide pharmacokinetic information from multi-component licorice/Kampo preparations rather than therapeutic evaluation of purified ISL. Drug-interaction potential involving CYP and UGT enzymes and weak estrogenic activity warrant caution.

Isoliquiritigenin Cancer-Relevant Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells Primary Effect Notes / Interpretation
1 PI3K / AKT / mTOR ↓ PI3K, ↓ p-AKT, ↓ mTOR signalling ↔ / context-dependent ↓ survival and proliferation; ↑ apoptosis/autophagy One of the most consistently implicated anticancer signalling axes; demonstrated in colorectal, gastric, breast, and other tumor models.
2 Mitochondrial apoptosis ↑ Bax, ↓ Bcl-2, ↑ cytochrome c, ↑ caspase-9/3/7, ↑ PARP cleavage Generally less cytotoxic at comparable lower exposures ↑ intrinsic apoptosis Frequently accompanies ROS accumulation and suppression of survival signalling.
3 JAK2 / STAT3 ↓ JAK2/STAT3 signalling ↔ / context-dependent ↓ proliferation and survival; ↑ apoptosis Supported in multiple tumor contexts and implicated in combination activity with chemotherapy.
4 ROS-mediated cancer stress ↑ ROS (model-dependent) ↓ oxidative stress or ↔ (context-dependent) ↑ mitochondrial injury and apoptosis ISL can function as a pro-oxidant in malignant cells while exerting antioxidant effects in inflammatory or neural models.
5 NF-κB inflammatory survival signalling ↓ NF-κB activation ↓ pathological NF-κB activation ↓ inflammatory survival signalling Contributes to antiproliferative, anti-inflammatory, anti-invasive, and neuroprotective effects.
6 AMPK / SREBF1 lipid synthesis ↑ AMPK, ↓ SREBF1, ↓ lipogenic enzymes Context-dependent ↓ fatty-acid synthesis and tumor growth Directly demonstrated in anaplastic thyroid carcinoma; consistent with metabolic stress induced by reduced ATP.
7 FGFR4 / FASN lipid metabolism ↓ FGFR4, ↓ FASN, ↓ PI3K/AKT Not established ↓ proliferation, migration, and lipid synthesis Recent colorectal-cancer evidence links FGFR4 suppression to inhibition of fatty-acid metabolic reprogramming.
8 EMT and metastatic phenotype ↑ E-cadherin; ↓ N-cadherin, vimentin, Snail-related signalling and MMP activity ↔ / context-dependent ↓ migration, invasion, and metastasis Observed across several tumor models; mechanisms intersect PI3K/AKT, NF-κB, STAT3, and β-catenin.
9 Cell-cycle regulation ↓ cyclins/CDKs; ↑ p21/p27 in selected models Mixed ↑ G1/S or G2/M arrest Exact arrest point varies with cell type and dose.
10 COX-2 / mPGES-1 / CYP4A11 ↓ enzymatic activity and downstream Akt/angiogenic signalling Potential anti-inflammatory activity ↓ eicosanoid-dependent angiogenesis Direct target engagement has been demonstrated in glioma models; reported enzyme inhibition is typically micromolar.
11 Angiogenic signalling ↓ VEGF-associated signalling ↓ stimulated endothelial angiogenic responses ↓ tumor angiogenesis Mechanistically plausible across several studies, although an influential older VEGF/VEGFR2 paper received an Expression of Concern in 2026 and should not be used as sole evidence.
12 NRF2 antioxidant response ↓ NRF2 in some radiosensitization models; otherwise mixed ↑ NRF2 under oxidative/inflammatory stress Context-dependent redox modulation Direction differs substantially by disease context. NRF2 activation is neuroprotective, whereas reduced NRF2 defence may increase cancer-cell oxidative sensitivity.
13 Radiosensitization ↑ radiosensitivity (model-dependent) Not established ↑ radiation-induced tumor damage Reported through modulation of Keap1/NRF2 and antioxidant capacity; remains preclinical.
14 Chemosensitization ↑ response to selected agents (model-dependent) Not established Potential combination therapy Recent lung-cancer work reports enhanced gemcitabine activity associated with suppression of JAK2/STAT3 signalling.
15 Estrogen receptor signalling ↑ ERα and ERβ transcriptional activity at some concentrations ↑ weak estrogenic signalling Mixed proliferative or antiproliferative effects Important caveat: low/intermediate ISL concentrations have stimulated proliferation of ER-positive MCF-7 cells, while higher concentrations become cytotoxic. ISL should not be treated as uniformly anti-estrogenic.
16 Clinical Translation Constraint High-micromolar effects often exceed expected parent-compound systemic exposure Potential CYP and UGT interactions Limits direct clinical translation Poor aqueous solubility, rapid glucuronidation, short parent-compound exposure, phytoestrogenicity, and absence of cancer efficacy trials are major constraints.


Alzheimer’s disease relevance: ISL has meaningful but still preclinical AD relevance. In Aβ42-stimulated microglia, it activates NRF2 while suppressing NF-κB, inflammatory cytokines, nitric oxide, and oxidative injury, indirectly protecting neuronal cells. More recent mouse evidence reports improved cognition together with reduced tau phosphorylation, oxidative stress, mitochondrial dysfunction, neuronal loss, and synaptic impairment. Evidence remains limited to cellular and animal models; there is no established human AD therapeutic evidence.

Primary AD mechanisms (ranked):

  1. Activation of NRF2 antioxidant defence with suppression of Aβ-associated oxidative stress.
  2. Suppression of NF-κB-driven microglial neuroinflammation and inflammatory cytokine production.
  3. Reduction of pathological tau phosphorylation in experimental AD models.
  4. Protection of mitochondrial function and cellular ATP homeostasis.
  5. Preservation of neuronal and synaptic markers with improvement of cognition in a mouse model.

Isoliquiritigenin Alzheimer’s-Relevant Mechanisms

Rank Pathway / Axis Modulation Primary Effect Notes / Interpretation
1 NRF2 antioxidant response ↑ NRF2 ↓ oxidative stress Demonstrated in Aβ oligomer-stimulated microglial models.
2 NF-κB neuroinflammation ↓ NF-κB ↓ inflammatory cytokines and nitric oxide Reduces Aβ-induced microglial inflammatory activation.
3 Tau phosphorylation ↓ pathological tau phosphorylation Potential reduction of tau-associated neuronal dysfunction Reported at Ser396 and Thr231 in a streptozotocin-induced mouse model.
4 Mitochondrial homeostasis ↑ mitochondrial functional preservation ↓ mitochondrial dysfunction and oxidative injury Associated with changes in DRP1, Mfn1, Mfn2, ATP, and ROS in experimental AD.
5 Synaptic integrity ↑ PSD95 and SNAP25 preservation ↓ synaptic impairment Preclinical mouse evidence only.
6 Clinical Translation Constraint No established human efficacy Limits therapeutic interpretation Evidence consists primarily of cell and animal studies; CNS exposure of pharmacologically active unconjugated ISL in humans remains insufficiently defined.


SREBP1/SREBF1, sterol regulatory element-binding protein 1: Click to Expand ⟱
Source:
Type:
SREBP1 is a key transcription factor that regulates genes involved in fatty acid and triglyceride synthesis. It primarily governs lipid metabolism by controlling the expression of enzymes required for de novo lipogenesis, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC), among others.
Two main isoforms—SREBP1a and SREBP1c—with SREBP1c being more involved in the regulation of lipogenesis in metabolic tissues.

Many cancers display elevated levels of SREBP1 activity. Increased expression or activation of SREBP1 supports the metabolic reprogramming that is characteristic of cancer cells, enabling them to meet the enhanced lipid requirements for membrane synthesis and energy storage during rapid cell proliferation.
Elevated SREBP1 activity is often linked to more aggressive cancer phenotypes. High SREBP1 levels can drive rapid proliferation, metastasis, and resistance to certain therapies, thereby correlating with poorer clinical outcomes in several cancers.

SREBF1 - Sterol Regulatory Element-Binding Transcription Factor 1 / SREBP-1

Abbreviation: SREBF1, SREBP-1, SREBP1

Type: Lipogenic transcription factor / basic helix-loop-helix leucine zipper transcription factor

Function: SREBF1 encodes SREBP-1, a master regulator of fatty-acid synthesis, lipid homeostasis, and metabolic gene expression. SREBP-1 is synthesized as an inactive endoplasmic-reticulum membrane precursor and, following SCAP-dependent processing and proteolytic cleavage, its active N-terminal transcription factor enters the nucleus. SREBP-1 regulates genes involved in de novo lipogenesis including FASN, ACACA/ACC, SCD1, and ACLY. The SREBF1 gene produces the SREBP-1a and SREBP-1c isoforms.

Cancer: ↑ Frequently increased or activated in cancer. Elevated SREBP-1 promotes de novo fatty-acid synthesis and metabolic reprogramming required for rapid tumor-cell proliferation. SREBP-1 can also promote survival, epithelial-mesenchymal transition, invasion, metastasis, tumor-microenvironment adaptation, ferroptosis resistance, and resistance to chemotherapy and radiotherapy. Genetic or pharmacological inhibition of SREBP-1 suppresses tumor growth in multiple preclinical cancer models.
Scientific Papers found: Click to Expand⟱
7744- ISL,    Isoliquiritigenin suppresses fatty acid synthesis and cancer cell migration in anaplastic thyroid carcinoma through AMPK/SREBF1 pathway
- vitro+vivo, Thyroid, NA
AntiTum↑, TumCP↓, TumCMig↓, E-cadherin↑, N-cadherin↓, FASN↓, SREBP1/SREBF1↓, ATP↓, p‑AMPK↑, lipidLev↓, TumCG↓, lipoGen↓,

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:


Mitochondria & Bioenergetics(tgid=3) ⓘ

ATP↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

p‑AMPK↑, 1,   FASN↓, 1,   lipidLev↓, 1,   lipoGen↓, 1,   SREBP1/SREBF1↓, 1,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

TumCG↓, 1,  

Migration(tgid=13) ⓘ

E-cadherin↑, 1,   N-cadherin↓, 1,   TumCMig↓, 1,   TumCP↓, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiTum↑, 1,  
Total Targets: 12

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: SREBP1/SREBF1, sterol regulatory element-binding protein 1
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#:425  Target#:1034  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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