Search Results (527)

Background/Objectives: Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) represent a growing public health concern. Both disorders are driven by mitochondrial dysfunction, oxidative stress, impaired autophagy, neuroinflammation, and neuronal loss. Single-target therapeutics have failed to halt disease progression, highlighting the need for multi-target interventions that address the complex and interconnected nature of neurodegeneration. Natural health products (NHPs) such as curcumin (CUR), coenzyme-Q10 (CoQ10), and Ashwagandha (ASH) possess antioxidant, anti-inflammatory, neuroprotective, and neurotrophic properties that may collectively address this complex pathology. However, poor bioavailability and hydrophobicity have limited clinical translations. Novel formulations, including nanomicellar Ubisol-Q10 (UQ) and water-solubilized ASH (PTS-ASH), have demonstrated enhanced metabolic uptake and neuroprotective efficacy in preclinical models. Moreover, co-administered NHPs, such as CUR + CoQ10 and CoQ10 + ASH, may provide further benefits by diversified targeting of disease pathways. Methods: This review presents an integrative interpretation of a combined UQ + ASH “tonic” in transgenic AD and paraquat-induced PD animal models using previously published qualitative immunohistochemical and functional results. This report constructs a proposed mechanistic model illustrating how these compounds may interact across multiple stages of disease AD and PD progression. Results: Based on comprehensive interpretation of the previous published reports, consistent trends suggest UQ stabilizes mitochondrial energetics and suppresses oxidative damage upstream, whereas ASH promotes downstream repair and synaptic modulation. Combined administration remained as providing balanced neuroprotective and functional outcomes. Conclusions: These interpretations of published reports and proposed mechanistic models aim to improve the translation and support the therapeutic potential of multi-component natural interventions for neurodegenerative diseases and highlight the importance of bioavailability-enhancing formulations in future preclinical and clinical research. Full article

Diabetic chronic wounds are often accompanied by excessive wound exudate maceration, which prolongs the inflammatory phase and increases the risk of infection. Such a complex wound microenvironment imposes more stringent requirements on multifunctional wound dressings. A multifunctional Cur Janus nanofibrous dressing is developed by integrating an electrospun poly(ε-caprolactone)/gelatin hydrophilic layer with a curcumin (Cur)-loaded PCL hydrophobic layer. Janus structure with asymmetric wettability, which exhibited unidirectional liquid transport properties both in vitro and in vivo. Its unique structure also makes it possible to carry both hydrophilic and hydrophobic drugs at the same time. The incorporation of curcumin endows the dressing with antibacterial and antioxidant functionalities, offering the potential to modulate the inflammatory microenvironment of diabetic chronic wounds. Furthermore, the wound healing ability and anti-inflammatory effects of Cur Janus nanofibers were evaluated in a diabetic mouse model. The results showed that Cur Janus nanofibers significantly reduced wound area, increased the proportion of pro-healing M2 macrophages, shortened the inflammatory phase, and ultimately accelerated diabetic wound healing. This work provides a multifunctional and scalable platform for advanced wound dressing design. Its excellent antibacterial, antioxidant (ROS scavenging) and anti-inflammatory (macrophage phenotype M1 to M2) properties, combined with the unidirectional fluid transport and dual-release potential of hydrophilic and hydrophobic drugs, demonstrate broad prospects in the management of diabetic wounds. Full article

Blue honeysuckle (Lonicera caerulea L.) is a polyphenol-rich berry increasingly recognized as a functional food ingredient for postprandial glycemic management. However, it remains unclear whether its polyphenols can modulate intestinal glucose transport in addition to inhibiting carbohydrate-digesting enzymes. In this study, blue honeysuckle polyphenol extract (BHPE) was characterized by UPLC-QTOF-MS/MS, and its effects on α-glucosidase activity and intestinal glucose transport were evaluated using enzyme kinetics, fluorescence quenching, molecular docking, and differentiated Caco-2 monolayers. A total of 24 phenolic compounds were tentatively identified, with anthocyanins and chlorogenic acid derivatives as the major constituents. BHPE exhibited a mixed-type, static-quenching inhibition of α-glucosidase (IC₅₀ = 75.05 μg/mL). Furthermore, molecular docking revealed that key constituents, including cyanidin-3-O-glucoside, chlorogenic acid, and proanthocyanidin B1, bind the enzyme via hydrogen bonding and hydrophobic interactions. In Caco-2 cell monolayers, BHPE reduced glucose transport by up to 51.56% under simulated postprandial conditions and coordinately downregulated SGLT1 and GLUT2 mRNA expression to 0.58- and 0.51-fold, respectively. These findings extend the bioactivity profile of blue honeysuckle polyphenols from enzyme-level inhibition to functional regulation at the intestinal epithelial barrier, highlighting their potential as multi-target natural ingredients for the attenuation of postprandial hyperglycemia. Full article

Gao-shan-hong-jing-tian (GSHJT) Oral Liquid is a phytochemical-rich preparation derived from Rhodiola, yet its anti-hypoxic active constituents and molecular mechanisms remain poorly understood. This study aimed to identify the key anti-hypoxic phytochemicals in GSHJT Oral Liquid and clarify their mechanisms of action to support its potential use in managing acute mountain sickness (AMS). We first established and validated an HPLC method for quality control, then comprehensively profiled the chemical composition using LC-MS. Network pharmacology and molecular docking were applied to predict the core anti-hypoxic components, candidate targets and signaling pathways. The primary bioactivity was further verified through an in vitro carbonic anhydrase (CA) inhibition assay. A total of 71 constituents were identified, with kaempferol and ellagic acid emerging as the primary anti-hypoxic phytochemicals. These compounds target seven core proteins (SRC, PIK3R1, ESR1, EGFR, PTK2, IGF1R, and LYN) to regulate vascular tone, inflammation, oxidative stress, blood–brain barrier integrity, and cell survival under hypoxic conditions. By modulating pathways such as HIF-1α, PI3K/AKT, FAK/PTK2, SRC, and IGF1R, these phytochemicals ultimately influence the onset and alleviation of AMS. Enzyme inhibition assays demonstrated that kaempferol and ellagic acid inhibited CA with IC₅₀ values of 34.05 μM and 119.1 μM, respectively. Molecular docking further revealed that both compounds suppressed CA activity through a combination of hydrogen bonding and hydrophobic interactions, consistent with a zinc-bound water-anchoring mechanism. This study elucidates the phytochemical basis and molecular mechanism responsible for the anti-hypoxic effects of GSHJT Oral Liquid, providing scientific support for its potential application as a natural, plant-derived intervention for preventing and alleviating acute mountain sickness, providing scientific support for its potential application and offering a reproducible paradigm for the rational development of other Rhodiola-based phytomedicines, though further in vivo validation is required to confirm the anti-hypoxic efficacy. Full article

Fruit and vegetable processing by-products, such as peels and pomace, are rich in antioxidant polyphenols and represent promising sources of functional ingredients, but how their galloyl-based polyphenols interact with starch remains insufficiently understood. In this study, corilagin with three non-free galloyl moieties and 1,2,3,4,6-O-pentagalloyl glucose with five free galloyl moieties were used as model polyphenols to clarify how galloyl moiety number and accessibility modulate their complexation with high-amylose maize starch (HAMS). Size-exclusion chromatography showed that both polyphenols preferentially complexed with amylose, while FTIR confirmed that complex formation occurred mainly through non-covalent interactions. The two polyphenols induced distinct changes in HAMS structure. Corilagin disrupted short-range order and produced no detectable crystalline structure, whereas 1,2,3,4,6-O-pentagalloyl glucose enhanced molecular order and induced V-type crystallization. Isothermal titration calorimetry revealed more binding sites but weaker affinity for corilagin, with thermodynamic signatures indicating hydrogen bonding and van der Waals interactions. By contrast, 1,2,3,4,6-O-pentagalloyl glucose showed stronger affinity and hydrophobic interaction-dominated binding. Molecular dynamics simulations further confirmed that 1,2,3,4,6-O-pentagalloyl glucose formed a more stable association with the amylose helix than corilagin. These results indicate that galloyl moiety characteristics markedly influence starch–polyphenol interaction mechanisms, providing guidance for the utilization of polyphenol-rich agro-processing by-products in functional starch-based foods. Full article

A critical yet frequently overlooked factor is the tumor’s metabolic profile. Diabetes and chronic moderate hyperglycemia are known risk factors for triple-negative breast cancer (TNBC) that do not respond to hormonal therapy. So, identifying novel therapeutic targets and developing more effective treatments is needed. One of the key pathways involved in the aggressive nature of TNBC is the Toll-like receptor 4 (TLR4) signaling cascade. To this end, curcumin (CUR) has shown effects consistent with modulating inflammatory stress by inhibiting TLR4/MD-2. This study evaluated CUR at concentrations observed in the bloodstream (0.025–25 ng/mL) in MDA-MB-231 TNBC cells under different glucose conditions (normal, moderate, and severe hyperglycemia) and inflammatory states (LPS-induced), using cell viability assays and molecular docking. A zinc complex (Zn–CUR) was also used. Results were validated through cell viability assays. Under severe hyperglycemia, CUR unexpectedly increased cell viability in a dose-dependent manner, while Zn–CUR had no activity across all glucose levels. In LPS-induced inflammation, CUR exhibited a biphasic, dose-dependent response, being protective at mid-level doses but cytotoxic at higher doses, whereas Zn–CUR showed more consistent effects, consistent with modulation of inflammatory stress. Molecular docking suggests that Zn–CUR binds more stably within the MD-2 hydrophobic pocket than CUR, particularly when bound to LPS, with binding energies of −8.7 and −8.3 kcal/mol, respectively. However, better in silico affinity did not always translate into improved cellular effects. These findings indicate that metabolic context significantly influences CUR’s biological activity and that forming a zinc complex offers a safer, more reliable profile. This positions Zn–CUR as a candidate warranting further investigation for TNBC, particularly in the context of hyperglycemia. Full article

Cyclodextrins (CDs) have emerged as important encapsulation platforms in dermatologic and cosmetic sciences, addressing critical challenges related to the solubility and stability of bioactive compounds. This review (Part I) systematically explores the relationship between the molecular architecture of CDs and their functional performance at the skin interface. A comprehensive analysis of the physicochemical properties of natural and derivative cyclodextrins is presented, alongside an evaluation of their interaction mechanisms with the skin barrier and current regulatory frameworks. This study highlights how the hydrophobic cavity of CDs enables the successful encapsulation of botanical extracts, significantly enhancing their bioavailability and photostability. Furthermore, the mechanistic insights provided clarify how appropriately selected and formulated CDs can modulate skin penetration while maintaining acceptable epidermal barrier compatibility. A critical synthesis of safety data and toxicological profiles confirms the suitability of specific CD types for topical application, supported by an overview of the evolving European and international legislative landscapes. Understanding the molecular design and safety constraints of cyclodextrin-based systems is essential for developing next-generation dermocosmetics. This foundational analysis provides the necessary framework for the clinical and technological applications discussed in the subsequent part of this review. Full article

The global rise in metabolic disorders demands novel interventions targeting starch digestion. This study investigated two dietary phenolic acids (caffeic acid (CA) and p-hydroxycinnamic acid (p-HA)) as inhibitors of α-amylase and α-glucosidase through integrated experimental and computational approaches. Molecular docking showed distinct binding modes, and CA formed stable hydrogen bonds with catalytic residues of α-glucosidase, while p-HA interacted mainly with α-amylase via hydrophobic contacts. Enzyme kinetics revealed concentration-dependent mixed-type inhibition, with CA being more potent against α-glucosidase and p-HA against α-amylase. Spectroscopic analysis indicated both acids induced structural changes in the enzymes, with CA causing greater α-helix reduction (Δ7.03% vs. Δ2.10%) by altering the tryptophan microenvironment. Moreover, both compounds significantly suppress glucose absorption in the proximal small intestine in an ex vivo everted gut sac model, with p-HA exhibiting exceptional efficacy in the duodenum. These findings clarify structure–activity relationships and support the potential use of CA and p-HA as local intestinal agents for modulating carbohydrate absorption. Full article

Immune checkpoint modulation has emerged as a promising strategy in cancer therapy, including the treatment of aggressive tumors such as glioblastoma. Among these targets, programmed death-ligand 1 (PD-L1) plays a key role in tumor immune evasion and represents an attractive target for small-molecule inhibitor development. In this study, a virtual screening approach was applied to identify potential PD-L1 modulators within a library of nucleoside-related compounds and structurally similar molecules. A dataset of 400 compounds was evaluated using molecular docking to predict their binding affinity (free energy values and binding pose) toward PD-L1. The resulting complexes were analyzed to identify nonbond interactions within the hydrophobic pocket formed at the PD-L1 dimer interface. In addition to docking results, physicochemical descriptors associated with drug-likeness and blood-brain barrier penetration were calculated, including lipophilicity, molecular weight, hydrogen bond donors and acceptors, as well as topological polar surface area. To integrate these parameters, a multiparameter optimization (MPO) score was implemented. Finally, molecular dynamics simulations of protein-ligand interactions were performed to explore the structural stability for 100 ns using the most promising ligands. The analysis revealed that several top-ranked compounds exhibited favorable docking scores and physicochemical properties compatible with drug-like behavior. Interestingly, BMS-1, a known PD-L1 inhibitor, was identified among the highest-scoring compounds, supporting the reliability of the MPO protocol. Furthermore, multiple candidates displaying nucleoside-like scaffolds combined with reduced polarity and moderate lipophilicity emerged as promising molecules according to the MPO ranking. Overall, the results suggest that nucleoside-derived scaffolds may represent a viable starting point for the development of small-molecule PD-L1 modulators with potential applicability in glioblastoma therapy. Full article

The Atlantic blue crab (Callinectes sapidus) is an invasive species widely distributed in the Mediterranean Sea, causing significant ecological and economic impacts. Despite its low commercial value and the limited utilization of undersized and non-marketable specimens, whole blue crab biomass represents a promising resource for the production of value-added compounds within a circular bioeconomy framework. In this study, whole blue crab biomass, including undersized individuals and non-marketable fractions, was directly valorized through enzymatic hydrolysis for the production of protein hydrolysates. Three commercial proteases (Alcalase, Neutrase, and Papain) were comparatively evaluated for protein hydrolysate production, and the hydrolysis conditions were assessed based on soluble matter yield. The evaluation of hydrolysis conditions identified pH 8, 50 °C, enzyme-to-substrate ratio of 2500 U g⁻¹, a solid-to-liquid ratio of 1:4, and a reaction time of 8 h as the most effective conditions for protein solubilization. Under these conditions, maximum soluble matter yields of 57.69% for Alcalase, 51.64% for Neutrase, and 48.44% for Papain were obtained. The obtained hydrolysates were subsequently characterized in terms of protein content and degree of hydrolysis (DH), both of which were significantly affected by enzyme type, following the order Alcalase (64.59 ± 0.75%) > Neutrase (62.29 ± 0.82%) > Papain (58.88 ± 0.65%). A similar trend was observed for degrees of hydrolysis (DH) of the products (43.20 ± 1.24%, 40.29 ± 1.05%, 37.26 ± 1.13%) respectively. Techno-functional properties of the hydrolysates were also enzyme-dependent and closely related to the extent of hydrolysis. Alcalase produced hydrolysates with higher DH, favoring the formation of smaller and more hydrophilic peptides, which enhanced water solubility (98.18 ± 0.51%) and antioxidant activity (77.08 ± 1.06%). In contrast, Papain-derived hydrolysates showed lower hydrolysis extent, likely preserving larger peptide structures and hydrophobic domains associated with higher emulsifying activity (16.10 ± 0.46 m² g⁻¹) and foaming capacity (30.47 ± 1.40%). Neutrase displayed intermediate behavior across most parameters. Overall, the results demonstrate that enzymatic hydrolysis of whole blue crab biomass is an effective valorization strategy, and that enzyme selection plays a key role in modulating hydrolysis efficiency and techno-functional properties. This approach provides a sustainable pathway for the management of invasive species while generating functional ingredients for food and nutraceutical applications. Full article

Telmisartan (TEL) is a non-peptide, orally administered antihypertensive agent primarily known as angiotensin II type 1 (AT1) blocker. In this review, we provide a detailed overview of how TEL modulates voltage-gated Na⁺ current (I_Na) and affects action potential (AP) firing behavior. TEL exerts differential stimulatory effects on the peak and late components of I_Na when subjected to brief depolarizing pulses across a range of cell types, such as mHippoE-14 hippocampal neuron, cultured dorsal root ganglion neurons, and HL-1 atrial cardiomyocytes. TEL can augment the non-inactivating (persistent) I_Na elicited by ascending long ramp pulse in mHippoE-14 cells. By using a parvalbumin-expressing interneuron-based modeled cell combined with bifurcation analysis, it is possible to predict how applied current influences subthreshold oscillations and the generation of somatic spiking in the presence of TEL. According to the Hodgkin-Huxley model, mimicking the action of TEL—characterized by an increased peak amplitude of I_Na and a slowed inactivation time course—leads to the emergence of periodic oscillations in membrane potential. Using a Markovian process, a separate model can also be mathematically constructed, showing that changes in certain rate constants can simulate the effect of TEL on I_Na in cardiac cells. The molecular docking prediction between TEL and the Na_V1.7 channel was made by expected formation of hydrophobic interactions as well as hydrogen bonding. In addition to its antagonistic action at the AT1 receptor and its agonistic activation of peroxisome proliferator-activator-γ, TEL may also directly enhance I_Na, thereby modulating AP firing in a variety of excitable cells. Current evidence supports TEL’s modulatory impact on Na_V channel activity and cellular excitability, while also acknowledging that the mechanism—whether direct or indirect—remains under investigation. Full article

To address wellbore instability and the technical challenges associated with high-density water-based drilling fluid loss control in deep shale gas formations of the Sichuan-Chongqing region in China, a novel nano-micro sealant designated CLG-Seal was synthesized via molecular structural optimization. The molecular structure of newly developed CLG-Seal exhibits distinct core–shell structural characteristics. The inorganic nano-silica constitutes the rigid core of CLG-Seal, which guarantees its plugging performance. The hydrophobically associating polymer which is coated on the surface of nano-silica constructs the flexible shell of CLG-Seal, endowing the CLG-Seal with excellent gel-forming capacity, adhesion film-forming capacity, deformability and perfect dispersibility. Transmission electron microscopy and scanning electron microscopy were employed to characterize the morphology of the CLG-Seal nanomicron-scale plugging agent. The sealing performance and underlying mechanisms of CLG-Seal were subsequently evaluated via particle plugging apparatus tests, displacement experiments, and etched glass micromodel simulations. Field trials conducted in the third section of Well WY3-2-3HF validated the application effectiveness of this agent in drilling fluid systems. The results indicate that the nano-micro sealant CLG-Seal exhibits a median particle size of D₅₀ is 146 nm, which can be modulated by adjusting the synthesis conditions. The nano-micro sealant CLG-Seal significantly mitigates fluid loss in low-permeability microfractures and fissures. Notably, a concentration of merely 3% is sufficient to achieve optimal nano-micro plugging performance. The results of the mechanism study indicate that while the CLG-Seal particles are close to each other, the polymer chains with flexible long chain structure which are coated on the surface of nano-silica constructs tend to be intertwined, forming a cross-linked network structure of gel film, thereby increasing the interaction between nano-micron particles and forming an impermeable plugging film. In addition, due to the nanoscale effect, the CLG-Seal has a strong tendency to adsorb onto the surface of shale rock through hydrogen bonding with the shale matrix. The hydrophobically associating polymer with high elastic modulus and excellent mechanical properties can enhance the pressure-bearing capacity of the filter cake through elastic deformation. Therefore, these nano-micron particles can form a strong sealing film on the filter cake and at the micropores of shale rock, thereby creating a dense mud cake on the outside of the shale formation. Field trial results demonstrate that the incorporation of the nano-micro sealant CLG-Seal into the drilling fluid for the third section of Well WY3-2-3HF reduced the PPA fluid loss to 4.6 mL. This value represents a substantial reduction compared to adjacent wells and signifies a remarkable improvement over the drilling fluids previously employed in the Longmaxi Formation of this block. Furthermore, the treated drilling fluid exhibited a superior filtration control pressure capacity of 10.5 MPa. The operation was completed successfully without any lost circulation or wellbore instability, and achieved a drilling footage of 42 h with an average penetration rate of 7.81 m/h. The mud weight was reduced by approximately 0.08–0.10 g/cm³ compared to offset wells. These results confirm the excellent application efficiency of the newly developed CLG-Seal in field operations. Full article

Background/Objectives: BRI is a synthetic arylamide polymer designed to mimic the electrostatic and amphiphilic features of defensin-type antimicrobial peptides (AMPs), although its molecular organization and activity have not been experimentally validated. This study presents the first integrated computational and experimental characterization of BRI to define the physicochemical basis of its AMP-like behavior and membrane interactions. Methods: Molecular modelling was used to evaluate the structural and electrostatic properties of BRI. Model lipid membranes were used to study membrane interactions. Fluorescence spectroscopy, electrochemical measurements, and ζ-potential analyses were performed to characterize membrane insertion, aggregation, ionic conductance, and membrane resistance. Microbiology assays evaluating synergy with azole were also assessed. Results: Molecular modelling showed that BRI is a flexible molecule with cationic and hydrophobic surfaces, a strong amphiphilic dipole, and a dominant +4 charge state, explaining its sensitivity to ionic strength and membrane interactions. BRI displayed two membrane-dependent mechanisms of action. In zwitterionic phospholipid membranes, BRI resembled canonical AMPs, showing membrane insertion, pore formation, and increased ionic conductance. In anionic ergosterol-containing membranes mimicking fungal cells, BRI exhibited sterol-dependent insertion, in-plane aggregation, and modulation of membrane resistance without pore formation. Fluorescence, electrochemical, and ζ-potential measurements supported BRI–BRI interactions at the membrane interface and sensitivity to lipid domain organization. BRI also synergized with azole antifungal drugs, suggesting a mechanistic role for ergosterol in its antifungal activity. Conclusions: These findings reveal a sterol- and domain-mediated mechanism for arylamide polymers and identify lipid organization as a key determinant of antifungal activity. The dependence of BRI activity on ergosterol content provides a mechanistic explanation for its synergy with azole antifungals and supports further investigation of BRI as a membrane-active antifungal agent. Full article

Cancer is a complex and evolutionary disease, with the development of different types of cancers leading to various different defective gene mutations. Synthetic lethality is a genetic-level precision medical strategy. Currently, treating BRCA (BReast CAncer)-mutated breast or ovarian cancer cells with a chemical inhibitor (Poly(ADP-ribose) polymerase, PARPi) is a typical synthetic lethal application in clinical practice. However, PARPi therapy has been found to cause off-target effects and therapy-induced immune escape driven by PD-L1 upregulation, allowing for cancer cells to escape attack from the immune response. To overcome these challenges, we developed a core–shell structure comprising a hydrophobic core of quercetin (Q)-mediated PARP inhibition and iron oxide nanoparticles (IONPs), enveloped by a hydrophilic fucoidan (Fu) shell to encapsulate short hairpin RNA targeting Programmed Death Ligand 1 (shPD-L1) for efficient gene transfection (shPD-L1@QIO@Fu). Structurally, the incorporation of quercetin into the intermediate hydrophobic layer enables modulate of the PARP effect, while the inner aqueous core with shPD-L1 gene silencing can inhibit the expression of PD-L1 protein. In this study, we proved that shPD-L1@QIO@Fu demonstrated a dual therapeutic mechanism against BRCA-mutant cancer cells by inducing extensive DNA double-strand breaks and promoting apoptosis. Furthermore, the combined action of quercetin-mediated DNA damage and shPD-L1-driven PD-L1 suppression led to a significant reduction in PD-L1 mRNA to approximately 5% at 72 h and decreased surface PD-L1 below baseline by 96 h. This effectively suppresses PARPi-induced PD-L1 upregulation and enhances antitumor immunity. These findings demonstrate the therapeutic efficacy of shPD-L1@QIO@Fu nanomedicine, providing a promising foundation for advanced co-delivery strategies to synergize PARP inhibition mediated synthetic lethality with immune checkpoint blockade in next-generation precision medicine. Full article

The tumor suppressor protein phosphatase 2A (PP2A) plays a crucial role in regulating oncogenic signaling. Its inactivation, specifically through inhibitory phosphorylation at Tyr307 mediated by SET and CIP2A, contributes to breast cancer (BC) progression. Modulation of these interactions represents a promising pharmacological strategy to restore PP2A function. We integrated computational approaches with experimental validation to analyse SET/CIP2A mechanisms and explore how PP2A reactivation suppresses tumor progression. Molecular docking and dynamics simulations showed that the SET inhibitor/FTY-720 forms stable hydrogen bond networks with SET, disrupting its interaction with PP2A. In contrast, CIP2A suppressor/erlotinib interacts with CIP2A through weaker hydrophobic and π-interactions. Protein–protein interaction analyses indicate reduced SET/CIP2A binding to PP2A upon treatment, supporting a structural basis for PP2A reactivation. Gene expression analyses revealed upregulation of PP2A, SET, CIP2A, and cytoskeletal markers in tumor and metastatic tissues. Studies on Triple Negative Breast Cancer (TNBC) cells showed that FTY-720 and erlotinib significantly reduce PP2A-Tyr307 phosphorylation, restoring its activity. Additionally, both compounds decreased c-Myc levels and inhibited Src/FAK/paxillin/PAK1 and ERK signaling, attenuating migratory and proliferative pathways. Our findings identify the SET/CIP2A–PP2A axis as a pharmacological target for the design of next-generation PP2A activators, highlighting the potential of inhibition as a therapeutic strategy to counteract TNBC progression. Full article