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| 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):
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
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):
Isoliquiritigenin Alzheimer’s-Relevant Mechanisms
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| Oxidative phosphorylation (or phosphorylation) is the fourth and final step in cellular respiration. Alterations in phosphorylation pathways result in serious outcomes in cancer. Many signalling pathways including Tyrosine kinase, MAP kinase, Cadherin-catenin complex, Cyclin-dependent kinase etc. are major players of the cell cycle and deregulation in their phosphorylation-dephosphorylation cascade has been shown to be manifested in the form of various types of cancers. Many tumors exhibit a well-known metabolic shift known as the Warburg effect, where glycolysis is favored over OxPhos even in the presence of oxygen. However, this is not universal. Many cancers, including certain subpopulations like cancer stem cells, still rely on OXPHOS for energy production, biosynthesis, and survival. – In several cancers, especially during metastasis or in tumors with high metabolic plasticity, OxPhos can remain active or even be upregulated to meet energy demands. In some cancers, high OxPhos activity correlates with aggressive features, resistance to standard therapies, and poor outcomes, particularly when tumor cells exploit mitochondrial metabolism for survival and metastasis. – Conversely, low OxPhos activity can be associated with a reliance on glycolysis, which is also linked with rapid tumor growth and certain adverse prognostic features. Inhibiting oxidative phosphorylation is not a universal strategy against all cancers. Targeting OXPHOS can potentially disrupt the metabolic flexibility of cancer cells, leading to their death or making them more susceptible to other treatments. Since normal cells also rely on OXPHOS, inhibitors must be carefully targeted to avoid significant toxicity to healthy tissues. Not all tumors are the same. Some may be more glycolytic, while others depend more on mitochondrial metabolism. Therefore, metabolic profiling of tumors is crucial before adopting this strategy. Inhibiting OXPHOS is being explored in combination with other treatments (such as chemo- or immunotherapies) to improve efficacy and overcome resistance. In cancer cells, metabolic reprogramming is a hallmark where cells often rely on glycolysis (known as the Warburg effect); however, many cancer types also depend on OXPHOS for energy production and survival. Targeting OXPHOS(using inhibitor) to increase the production of reactive oxygen species (ROS) can selectively induce oxidative stress and cell death in cancer cells. -One side effect of increased OXPHOS is the production of reactive oxygen species (ROS). -Many cancer cells therefore simultaneously upregulate antioxidant systems to mitigate the damaging effects of elevated ROS. -Increase in oxidative phosphorylation can inhibit cancer growth. |
| 7761- | ISL, | Targeting digestive system cancers with isoliquiritigenin: a comprehensive review of antitumor mechanisms |
| - | Review, | Var, | NA |
| 7760- | ISL, | Pharmacological Potentials and Delivery Strategies of Isoliquiritigenin: Challenges and Advances in Enhancing Bioavailability |
| - | Review, | Nor, | NA |
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
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