Copper is an essential element for living organisms, being a cofactor for numerous enzymes or proteins involved in oxidation-reduction reactions, intervening in numerous metabolic processes. In recent decades, complex copper combinations have consolidated their position in medicinal chemistry, which is manifested by the increasing number of compounds that have demonstrated their efficacy following in vitro or in vivo testing. While attempting to mimic the DNA-metal complex interactions typical of cisplatin, most studies of the mechanisms of action of copper complexes continue to consider DNA as the main biological target. Starting from this, studies are focused on understanding in detail how copper complexes manage to destroy tumor cells, and this has led to the discovery of a wide range of such mechanisms of antitumor action. In this review we present the main mechanisms of action of copper complexes discovered in recent decades, from the most well-known (production of ROS following the reaction with DNA) to the newest (cuproptosis). Research into understanding the mechanisms of action of copper complexes continues to be a topic of great interest in developing new potential antitumor agents.

Proliferating cell nuclear antigen (PCNA) is a critical regulator of DNA replication and repair, and its cancer-associated isoforms represent promising therapeutic targets. The small molecule AOH1996 has been previously reported as a PCNA inhibitor with potent antiproliferative activity. Here, a series of novel AOH1996-based structural analogs were synthesized using structure-activity relationship (SAR) and scaffold-hopping strategies, including 1,2,3-triazole, glycine, and amide derivatives with diverse aromatic and polar substituents. The antiproliferative activity of these compounds was evaluated in MCF-7 (breast cancer) and U87 (glioblastoma) cell lines using the MTT assay. The parent compound AOH1996 exhibited the strongest cytotoxicity, reducing cell viability below 30% at 10 μM. Among the analogs, compounds 1f, 2b, 3b, 3c, and 3d demonstrated significant activity, reducing MCF-7 viability by 60-70% and U87 viability to 30-40% at 10 μM. SAR analysis revealed that electron-withdrawing or moderately lipophilic substituents on the amide side chain and aromatic extensions on the triazole ring enhanced potency, while bulky or strongly electron-donating groups diminished activity. ADMET predictions indicated that most derivatives possessed favorable drug likeness and absorption potential, but high plasma protein binding, short predicted half-lives, and potential cardiotoxicity represent limitations that will require further optimization. Several active compounds were predicted to inhibit P-glycoprotein, suggesting their potential to overcome multidrug resistance. Overall, compounds 2b and 3b showed relatively favorable predicted profiles and can serve as useful lead scaffolds for further optimization and experimental validation.

Creole avocado (Persea americana var. drymifolia) seeds are considered as biowaste; however, they constitute a rich source of bioactive compounds. The objective of this study was to evaluate the cytotoxic effect of extract, partitions, and acetogenin mixture from creole avocado seeds in SiHa cells and erythrocytes. Creole avocado seed extract was obtained using ethyl acetate (CASE), and subsequently partitioned into hexane (HP), ethyl acetate (EP), and butanol (BP). Acetogenin mixture (AM), composed of avocadene acetate and avocadyne acetate, was isolated from HP and structurally characterized. Total phenolic content, antioxidant capacity and cytotoxic effect of all samples were evaluated using SiHa cell line and human erythrocytes. BP exhibited the highest total phenol content with a value of 159.13 mg of gallic acid equivalents/g (mg GAE/g). Antioxidant capacity assessed by 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) and 2,2-diphenyl-1-picrylhydrazyl (DPPH•) assays indicated that BP showed the greatest antioxidant capacity with values of 207.26 and 94.96 mg of Trolox equivalents antioxidant capacity/g (mg TEAC/g), respectively. AM demonstrated the highest cytotoxicity against SiHa cells at all exposure times, with half-maximal inhibitory concentration (IC50) values ranging from 15.37 to 28.09 µg/mL. Half-maximal hemolytic concentration (HC50) of all samples ranged from 107.39 to 160.26 µg/mL. AM, isolated from creole avocado seeds, showed the highest cytotoxic activity against SiHa cells, highlighting its potential as a promising bioactive compound for further investigation in cancer research.

Current cancer treatments have significant limitations. Designing TPP+-modified, mitochondrial-targeted drugs can improve anticancer efficacy. Although wogonin exhibits antitumor activity, it has drawbacks, including poor solubility and limited distribution. This study designed and synthesized 27 derivatives, including nine novel wogonin triphenylphosphine derivatives that demonstrated in vitro antitumor activity. Mito-WO-8, one of these derivatives, exhibited potent activity against PC-3M cells (IC50 = 3.19 μmol/L), demonstrating 15-fold higher potency than wogonin. Further analysis revealed that Mito-WO-8 accumulates more in mitochondria than wogonin and induces mitochondrial dysfunction, including increased reactive oxygen species, reduced membrane potential, and activation of the MPTP channel. Transcriptome and network analyses revealed that Mito-WO-8 activates the p38/MAPK pathway. Downregulation of p-MKK6 and p-p38, as well as upregulation of DDIT3 and cleaved caspase-3, were validated by Western blot (WB) and quantitative polymerase chain reaction (qPCR). Therefore, Mito-WO-8 enhances mitochondrial enrichment and induces mitochondrial damage. This process is associated with apoptosis and the activation of the ROS-p38/MAPK pathway. Additionally, the study found that Mito-WO-8 exhibits a stronger binding affinity for mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2) than the parent compound (-9.6 kJ/mol vs. -6.6 kJ/mol), suggesting a potential interaction with GPD2. This finding establishes a foundation for further investigation into its targeted antitumor mechanism.

This study developed pH/enzyme-sensitive polymeric HA-AAN-DOX (HAD) micelles to resolve the limited targeting specificity of chemotherapy drugs.

Tubulin is a heterodimeric protein composed of α- and β-subunits, which polymerize to form the cell's microtubules. The latter are key components in mitotic spindle formation and essential targets in anticancer therapy. Compounds such as paclitaxel, tubulysins, dolastatins and synthetic analogues of these latter compounds, including cemadotin, exert their cytotoxic effects by disrupting microtubule dynamics. Previously, we reported the production and anticancer activity of a library of cemadotin analogues featuring a C-terminal tertiary amide functionalized with a variety of N-substituents, thus resulting in compounds occurring as a mixture of amide rotamers. Here we describe a comprehensive NMR and conformational study that provides new insights into the effect of the conformational equilibrium on the binding mode of the novel cemadotin analogues to the tubulin target. The conformational behavior of the isomer equilibrium of cemadotin's terminal amide bond was investigated by TOCSY and ROESY NMR experiments, which allowed the identification and quantification of individual rotamer populations. A slow interconversion between the s-cis and s-trans amide rotamers was observed under standard NMR conditions (25 °C), indicating a significant energy barrier and conformational rigidity. Molecular docking and saturation transfer difference (STD) NMR experiments were performed with a representative analogue and tubulin to assess the binding mode. The results revealed that the s-trans rotamer is the predominant conformer in solution and exhibits a more favorable interaction with tubulin compared to the s-cis isomer, thus helping to understand the conformational requirements for an improved tubulin binding and the inhibition of the polymerization process.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, necessitating the development of novel multi-targeted therapeutic agents. This study investigates the anticancer effects of Panax notoginseng extract (PNE) against CRC using an integrative approach of network pharmacology and experimental validation. Phytochemical profiling via LC-MS identified major ginsenosides, including Rb1, Rg1, and Rd. Network pharmacology analysis revealed potential targets such as Bcl-xL, STAT3/CDK1, and IL-2, which are associated with apoptosis, cell cycle regulation, and immune modulation, respectively. Experimental results demonstrated that PNE significantly inhibited the proliferation of HCT 116 and HT-29 CRC cells, induced G0/G1 phase arrest by modulating CDK4/6 and p21/p27, and promoted apoptosis by regulating BCL2 family proteins. Furthermore, PNE treatment suppressed tumor growth in a CT26-bearing syngeneic mouse model. These findings highlight that PNE exerts potent anticancer effects through multi-pathway modulation, suggesting its potential as a therapeutic candidate for CRC.

Cancer drug discovery continues to rely on the development of small molecules able to modulate key biological processes involved in tumor initiation and progression [...].

Garlic (Allium sativum L.) belongs to the Allium genus and is one of the main bulbous plants consumed fresh, powdered, or cooked. Numerous studies have shown that garlic exhibits antihyperlipidaemic, antioxidant, anti-inflammatory, cardiovascular disease preventive, antihypertensive, antibacterial, antiviral, antifungal, antiparasitic, antidiabetic, anticarcinogenic, hepatoprotective, immunomodulatory, and hypoglycaemic effects. Moreover, studies on polyphenols detected in garlic reveal strong anticancer properties in various cell lines. The aim of this review is to summarise the current state of knowledge regarding the anticancer properties and shared molecular mechanisms of action of garlic-derived polyphenolic compounds. Our analysis demonstrates that the polyphenol content in garlic is highly variable and depends on numerous factors, including the part of the plant, processing methods, place of cultivation, and other conditions. Additionally, garlic contains polyphenols that exhibit anticancer activity in preclinical models, the properties of which have been demonstrated in in vitro studies. The anticancer mechanism of action varies depending on the type of polyphenol. Several polyphenols from garlic such as e.g., catechin, quercetin, and kaempferol activate peroxisome proliferator-activated receptors, which appear to contribute to at least part of garlic's anticancer activity. The primary mechanism of garlic's anticancer properties relies on reactive oxygen species-dependent toxicity and/or apoptosis, and Nrf2 is also implicated in the mechanism of action of garlic polyphenols. Our review provides evidence that under in vitro conditions, polyphenols present in garlic may exhibit anticancer properties. Garlic is not only a valuable culinary ingredient but also a natural medicine. Regular consumption in moderate amounts may offer numerous health benefits.

Hydantoins, exemplified by the imidazolidine-2,4-dione core, are privileged scaffolds in medicinal chemistry due to their compact structure, versatile hydrogen-bonding capacity, ability to fine-tune physicochemical properties for drug-like molecules, and potential to engage a diverse array of biological targets. This review highlights major advances in hydantoin-based drug discovery since 2019, emphasizing their evolving applications in oncology; neurology; infectious diseases; and cardiovascular, metabolic, and immune disorders. Recent studies demonstrate their success as kinase inhibitors, androgen receptor antagonists, and metalloprotease inhibitors, and emerging roles in modulating sterol isomerase, glycogen synthase kinase-3β, and ADAMTS family enzymes. Novel hybrid scaffolds-such as catechol-hydantoins, β-carboline-hydantoins, and spirocyclic thiohydantoins-have yielded potent and selective anticancer and antiviral leads. The discovery of BAY-9835 and GLPG1972 underscores the clinical potential of hydantoin-based metalloproteinase inhibitors in cardiovascular and osteoarthritic conditions. Furthermore, new antimicrobial, antimalarial, and antileishmanial derivatives illustrate the scaffold's capacity to address multidrug resistance and neglected tropical diseases. Advances in computational design, stereochemical optimization, and hybridization strategies have expanded the structural and functional diversity of hydantoins, enhancing their target selectivity and pharmacokinetic profiles. Overall, hydantoins and their analogs remain at the forefront of small-molecule drug discovery, offering rich prospects for therapeutic innovation in diverse disease areas.

Vitamin D is widely recognized for its pivotal role in the prevention and treatment of various cancers. The active compounds derived from plants have garnered significant attention due to their multi-faceted anticancer properties. Given the complexity and heterogeneity of cancer, monotherapies often fall short in effectiveness. As a result, combinatorial pharmacological strategies, which utilize multiple drug agents, are increasingly being employed globally. Notably, emerging evidence highlights the potent synergistic anticancer effects of vitamin D in combination with certain phytochemicals against a variety of cancers. This review explores the cooperative mechanisms through which vitamin D and phytochemicals enhance cancer prevention and therapy. In addition to examining their synergistic effects, this review also discusses recent advancements in nanotechnology-based delivery systems for vitamin D, which hold promise for optimizing its therapeutic potential. Collectively, these findings underscore the potential of combining vitamin D with phytochemicals and innovative delivery methods as a promising strategy in the fight against cancer, paving the way for more effective, multi-targeted therapeutic approaches.

Naphthyridine derivatives have emerged as privileged scaffolds with diverse pharmacological activities, particularly in anticancer and antiviral drug discovery. In this study, a series of naphthyridine-based derivatives (1-10b) was designed, synthesized, and structurally characterized using IR, 1H/13C NMR, and mass spectrometry, and evaluated as dual-function antiproliferative and anti-fowlpox virus agents supported by integrated computational analyses. The synthesized compounds were screened for in vitro antiproliferative activity against HeLa, HCT-116, and MCF-7 cancer cell lines, as well as normal WI-38 lung fibroblasts. Several derivatives exhibited potent cytotoxic activity with enhanced selectivity toward cancer cells. Compound 5b showed the highest activity against HeLa cells, compound 1 was most effective against HCT-116 cells, while compounds 7 and 8 displayed remarkable activity against MCF-7 cells, with compound 7 surpassing doxorubicin and compound 8 demonstrating excellent selectivity toward normal cells. Mechanistic investigations revealed that compounds 7 and 8 acted as dual topoisomerase I/IIβ inhibitors, inducing G2/M cell cycle arrest and intrinsic apoptosis associated with caspase-9 activation and downregulation of topoisomerase II protein expression. Selected derivatives were further evaluated for antiviral activity against fowlpox virus using in ovo and in vivo SPF embryonated chicken egg models, where compounds 2 and 9a exhibited the highest therapeutic indices, comparable to ribavirin, and compound 9a markedly suppressed viral replication and titers in vivo. ADMET profiling, molecular docking, molecular dynamics simulations, and DFT calculations supported the experimental findings and identified compound 10a as the most favorable theoretical candidate. Overall, this integrated experimental-computational approach establishes naphthyridine derivatives as a rationally designed multifunctional chemotype for simultaneous anticancer and antiviral drug development.

Drug repurposing in oncology is often framed as a drug-target matching exercise, yet many candidates with plausible biological rationales fail in the clinic. In solid tumors, therapeutic outcomes are constrained not only by pharmacological target relevance but also by limited tumor accessibility, heterogeneous intratumoral exposure, loss of context-dependent activity, and dose-limiting systemic toxicity. This perspective argues that repurposing strategies should treat exposure engineering as a design principle alongside molecular selectivity. Peptides that bind cell- or matrix-associated molecules at the tumor site have the potential to implement spatial, temporal, and subcellular control over where and when a drug engages its pharmacological target, thereby enabling confinement of polypharmacology to tumor contexts. Mechanistic modes of peptide-enabled exposure selectivity (homing, anchoring/retention, conditional activation, penetration enhancement, and subcellular biasing), key failure modes, and translational constraints are discussed, together with an exposure-centric screening workflow to prioritize repurposed agents most amenable to peptide-guided rescue. Emphasizing the combination of exposure control and the addressing-element layer clarifies when and how pharmacologically promiscuous drugs may be repurposed safely and effectively.

Bone metastasis remains a fatal and incurable condition for patients with breast cancer, leading to skeletal deterioration. The bone microenvironment enhances tumor proliferation and chemoresistance, necessitating novel therapeutic strategies. To investigate the cytotoxicity of two phytochemically-enriched plant extracts: Origanum vulgare (O.V.) and Vaccinium macrocarpon (V.M.) against breast cancer cells in a bone-metastatic condition. MCF-7 and MDA-MB-231 cell lines were treated with O.V. and V.M. for 24 h, in both 2D and 3D bone metastatic conditions. Live cell imaging, Alamar blue viability assay, RT-PCR, and flow cytometry analysis were used to assess cytotoxicity, apoptosis activation, and changes in oxidative stress/mitochondrial activity. Both extracts significantly inhibited cancer cell growth in a dose-dependent manner, with differential sensitivity observed between cell lines. Based on IC50 analysis, O.V. demonstrated greater efficacy against the bone metastatic MCF-7 cell line, while V.M. was more effective against the bone metastatic MDA-MB-231. Apoptosis activation was confirmed via upregulation of pro-apoptotic proteins p53 and caspase-9. Importantly, we observed that normal bone cells were unaffected by the treatments. These findings elucidate the promising yet untapped potential of O.V. and V.M. extracts as robust therapies for bone metastasis.

Hedera helix (HE) contains diverse bioactive constituents, including triterpenoid saponins, flavonoids, and phenolic acids, which exhibit various pharmacological activities. In this study, ultrasound-assisted extraction (UAE) combined with natural deep eutectic solvent (NADES) was employed to enhance the extraction efficiency and elucidate the underlying mechanisms. Among the tested formulations, a ternary system composed of malonic acid (Mal), N,N'-dimethylurea (DMU), and 1,4-butanediol (1,4-BDO) achieved the highest efficiency for extracting eight target compounds from the HE leaves. In addition, the key interactions among NADES components were confirmed by Fourier-transform infrared (FT-IR) spectroscopy, providing valuable insights into the extraction mechanism. The UAE process was systematically optimized through single-factor experiments. Subsequently, response surface methodology (RSM) identified the optimal conditions as ultrasonic time of 45 min, solid/liquid ratio of 1:54 g/mL, and ultrasonic temperature of 42 °C. Scanning electron microscopy (SEM) elucidated the microstructural alterations in plant cell walls induced by NADES-UAE, alongside the enhanced penetration and disruption mechanisms. In vitro bioactivity revealed that the NADES-extracted HE exerted strong inhibitory effect on HT-29 colon cancer cells. Overall, these findings demonstrate the high effectiveness and sustainability of NADES-UAE for extracting HE bioactive compounds and provide valuable implications for the industrial-scale production of plant-based functional products.

Epigenetic dysregulation is increasingly recognized as a key driver of glioblastoma (GBM), with bromodomain-containing protein 4 (BRD4) emerging as a critical regulator of tumor malignancy. GBM is an aggressive brain tumor marked by diffuse infiltration, a population of stem-like cells and multiple resistance mechanisms, which together render it largely incurable. Standard treatment, consisting of surgical resection followed by radiotherapy and temozolomide chemotherapy, confers only limited therapeutic benefit, while a member of the bromodomain and extra-terminal (BET) family, BRD4, regulates transcriptional programs essential for oncogene activation, chromatin stability and glioma cell survival. Its expression is markedly elevated in GBM relative to normal brain tissue, implicating BRD4 in tumor initiation, progression and therapeutic resistance. Recent advances have enabled the development of selective BRD4 inhibitors and degraders capable of penetrating the blood-brain barrier and preferentially targeting glioma cells. Preclinical and early-phase clinical studies indicate that these agents suppress tumor growth and may enhance the efficacy of existing treatments. Although BRD4 clearly influences glioma progression and modulates key oncogenic pathways, the precise mechanisms underlying BRD4-driven gliomagenesis remain only partially understood. Ongoing research continues to advance knowledge of its multifaceted functions. This review summarizes current knowledge on BRD4 in GBM, evaluates emerging BRD4-targeted therapeutic strategies and outlines major challenges and future directions for clinical translation.

Cyanobacteria of the genus Phormidesmis are recognized as a promising source of biologically active secondary metabolites with anticancer and immunomodulatory properties. In the present study, we investigated both the cytotoxic and immunological effects of an extract obtained from Phormidesmis molle PACC (Plovdiv Algal Culture Collection) 8140 as well as its chemical composition. The extract was profiled by LC-ESI-MS/MS (Liquid chromatography-electrospray ionization-tandem mass spectrometry), and selected compounds were evaluated with in silico ADMET (Absorption, distribution, metabolism, excretion and toxicity) modeling. The cytotoxic potential of the extract was evaluated in vitro using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay on human colorectal adenocarcinoma cell lines (Caco-2, HT-29, and LS-180). The immunological impact of the extract was assessed on human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. PBMCs were treated with 100 µg/mL extract for 48 h, followed by flow cytometric immunophenotyping and ELISA (Enzyme-linked immunosorbent assay)-based cytokine quantification. The extract induced a concentration- and time-dependent decrease in cancer cell viability after 24, 48, and 72 h of exposure. At 72 h, treatment with the highest concentration (200 µg/mL) reduced cell viability to 74% in Caco-2 cells, 69-70% in HT-29 cells, and 59-61% in LS-180 cells. Morphological changes observed after treatment with Phormidesmis extract showed pronounced cytotoxic and apoptosis-related effects in the colorectal cancer cell lines tested. Immunophenotyping revealed a pronounced expansion of natural killer (NK) cells (CD56+ and/or CD16+). CD3-CD56-CD16+ NK population was markedly increased (from 67.7 ± 0.95% in non-treated PBMCs to 94.66 ± 0.90% in extract-treated PBMCs, p < 0.001). In contrast, the proportions of CD8+ T cells, CD19+ B cells, and CD11b+ monocytes were significantly reduced (from 21.5 ± 4.50% to 7.22 ± 0.41%, from 11.9 ± 1.70% to 6.06 ± 0.42%, and from 66.4 ± 0.60% to 34.4 ± 0.87%, respectively). Cytokine analysis demonstrated strong suppression of Th1-associated cytokines, with significantly reduced interferon gamma (IFN-γ, 461 ng/mL in controls vs. 84 ng/mL in extract-treated cultures) and tumor necrosis factor alpha (TNF-α) levels (169 ng/mL in controls vs. 32 ng/mL in extract-treated cultures), whereas nterleukin-6 (IL-6) was moderately elevated (from 158 ng/mL in controls to 234 ng/mL in extract-treated cultures) and IL-10 remained low. These findings demonstrate that P. molle extract combines cytotoxic activity against cancer cells with potent immunomodulatory effects, highlighting its potential as a source of bioactive compounds for immune-based therapeutic strategies.

Autophagy and paraptosis are two distinct physiological mechanisms involved in regulating cell fate in cancer. Recent studies have demonstrated that autophagy is a crucial process for maintaining cellular homeostasis by facilitating the removal of misfolded proteins and damaged organelles. However, autophagy is found to play a dual role in cancer. Severe ER and mitochondrial dysfunction can trigger different forms of programmed cell death, including autophagic cell death. In cancer cells that evade apoptosis, paraptosis, a caspase-independent alternate death pathway, is triggered by ER and mitochondrial swelling, leading to extensive cytoplasmic vacuolation. It can be induced by natural compounds, metallic complexes, nanoparticles, or chemotherapeutic agents, primarily through excessive ROS production and disruption of protein, thiol, and calcium/ion homeostasis. Autophagy and paraptosis have been found to be connected through crosstalk. While MAPK activation drives paraptosis, ER stress and the unfolded protein response (UPR) can initiate both paraptosis and autophagy. UPR-mediated PERK activation promotes survival autophagy in ER-stressed melanoma, whereas PERK elimination triggers paraptosis via sec61β with unresolved ER stress. Similarly, CHOP and DDIT4 can enhance ER stress and proteotoxicity, thereby favouring paraptosis. This review is unique in exploring the dynamic interplay between autophagy and paraptosis in cancer cells, highlighting promising therapeutic targets for chemotherapy-resistant cancers.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and remains highly lethal, with median overall survival rarely exceeding 15 months despite maximal surgical resection, radiotherapy, and temozolomide-based chemotherapy. Therapeutic resistance in GBM is driven by intrinsic tumor cell adaptations, extensive inter- and intratumoral heterogeneity, and microenvironmental constraints. Key mechanisms include enhanced DNA repair, disrupted apoptosis, pathway redundancy, altered drug metabolism, oxidative stress tolerance, and glioblastoma stem cell-mediated plasticity. In vivo, resistance is reinforced by the blood-brain barrier, hypoxia, stromal and immune interactions, and selective expansion of therapy-resistant clones. Current strategies to overcome resistance target DNA repair, oxidative stress, autophagy, and metabolic vulnerabilities; however, their efficacy is limited by tumor heterogeneity and delivery barriers. Precision oncology approaches are hampered by a paucity of validated predictive biomarkers, leaving many patients without actionable targets. Ex vivo functional drug sensitivity testing of patient-derived tumor cells offers a complementary strategy, directly assessing individual tumor responses and guiding rational combination therapies. This review highlights the molecular and cellular mechanisms underlying chemoresistance in GBM, examines emerging therapeutic strategies, and explores the potential of integrating personalized, functionally guided approaches into clinical management. Addressing GBM's profound heterogeneity and adaptive plasticity is essential to improving outcomes in this aggressive and refractory malignancy.

This study utilized network pharmacology, bioinformatics, along with machine learning to investigate the multi-target synergistic anti-cancer mechanisms of three edible medicinal plants (EMPs)-mulberry leaf, lotus leaf, and sea buckthorn-against oral and esophageal squamous cell carcinomas (OSCC and ESCC). We identified potential active constituents and their targets through mining Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Swiss Target Prediction databases. Concurrently, integration with differential expression profiles and co-expression modules identified crucial intersection targets between the EMPs and these two cancers. Subsequent machine learning algorithms and cross-cancer analysis consistently identified Matrix Metalloproteinase-1 (MMP1) as a critical hub gene. Its overexpression is closely associated with tumor invasion and metastasis. Molecular simulations revealed stable binding interactions between active constituents from three EMPs and hub proteins. Furthermore, research on immune cell infiltration suggested that the active components of three EMPs may impact the tumor immune microenvironment in both OSCC and ESCC through the regulation of pivotal gene expression. Collectively, this work systematically elucidates the molecular basis underlying the multi-target, multi-pathway synergistic anti-cancer effects of these EMPs, providing a theoretical foundation for developing natural drugs against these squamous cell carcinomas.