Pectolinarigenin (PEC) is a natural flavonoid compound derived from Chinese herbal medicines. Previous studies have demonstrated its significant inhibitory effects against various malignancies. However, the effect and molecular mechanism of PEC in esophageal squamous cell carcinoma (ESCC) as well as its potential for combination with clinical chemotherapeutics for ESCC treatment is still obscure. Here, we systematically explored the anti-ESCC effects of PEC, elucidated its molecular mechanism, and evaluated its synergistic therapeutic potential with paclitaxel (PTX), a first-line chemotherapeutic agent for ESCC. The results showed that PEC obviously restrained proliferation and migration, and induced apoptosis of ESCC cells. Mechanistically, we found that PEC targets the non-canonical pathway of NF-κB, specifically preventing nuclear translocation of p52 and RELB, thus suppressing the transcriptional activity of this pathway. Moreover, we confirmed that PEC markedly inhibited tumor growth and exhibited a strong synergistic effect on the progression of ESCC when combined with PTX using a xenograft model of nude mice. Our research results have revealed a new molecular mechanism for the anti-ESCC efficiency of PEC. This study highlights PEC potential as a promising candidate for ESCC monotherapy or combination therapy with PTX and points out a new strategy for the clinical treatment of natural flavonoids to ESCC.

Chemotherapy-induced adverse effects and drug resistance remain major obstacles limiting the therapeutic efficacy of cancer treatment, underscoring an urgent need for novel anticancer agents. Among promising candidate molecules, antimicrobial peptides (AMPs) exhibit considerable therapeutic potential owing to their unique mechanisms of action, potent anticancer activity, minimal off-target toxicity, and low propensity to induce drug resistance. In this review, we summarize recent advances in the anticancer properties of AMPs, with a focus on their effects on both cancer cells and immune cells across diverse cancer types, clinical applications, as well as current challenges and future prospects. This review highlights the promise of AMPs as highly effective anticancer candidates for combination cancer therapy.

Aberrant expression of mitochondrial quality regulation genes (MQRGs) is intricately linked to mitochondrial dysfunction and the progression of hepatocellular carcinoma (HCC), highlighting the urgent need for reliable prognostic biomarkers. In this study, we aimed to identify differentially expressed MQRGs from 20 candidate genes by analyzing transcriptomic profiles and clinical records from the TCGA (n = 371) and GEO (n = 167) datasets. The identified prognostic MQRGs, along with associated subtype differentially expressed genes (DEGs, n = 156), underwent LASSO and multivariate Cox regression analyses to construct a risk model, which was subsequently validated through time-dependent ROC analysis, Kaplan-Meier curves, and in vitro RT-qPCR. Our findings established a robust 4-MQRG signature comprising ANXA10, BAMBI, AKR1B15, and SPINK1, which revealed that patients classified as high risk had significantly shorter overall survival compared to their low-risk counterparts (p < 0.001). The predictive accuracy of this signature was noteworthy, yielding 1-, 3-, and 5-year AUCs of 0.725, 0.696, and 0.747 in the training cohort (n = 243) and 0.676, 0.627, and 0.592 in the testing cohort (n = 242), respectively. Furthermore, high-risk scores were associated with distinct immunosuppressive tumor microenvironments and varying sensitivity to systemic therapies. The dysregulated expression of the four genes was corroborated by RT-qPCR and analysis of the HPA database. In conclusion, this validated MQRG-based prognostic signature serves as an accurate tool for survival prediction and risk stratification, thus offering valuable biomarker support for personalized therapeutic approaches in HCC.

SND1 is an oncoprotein found to be overexpressed in breast cancer, especially in triple-negative breast cancer(TNBC). In our previous study, a novel SND1-interacting peptide 4-2 was identified, exhibiting cytotoxicity to TNBC cells by inducing SND1 degradation. This study for the first time demonstrated the degradation of SND1 was proteasome-dependent. A series of peptide 4-2 derivatives were constructed using PROTAC technology. Among these, 4-2 VHL-recruiting PROTAC showed significantly increased SND1 degradation efficiency and higher anticancer activity to TNBC cells. The in vivo efficacy study suggested the D-isoform of 4-2VHL PROTAC suppressed the growth of TNBC cells in xenograft mouse model more effectively than peptide 4-2. Mechanistically, 4-2 VHL-recruiting PROTAC was demonstrated to induce pyroptosis of TNBC cells through Fas-mediated IL-17signaling. This study provides a new lead compound for the development of theSND1-targeted therapy via the proteolysis-targeting system.

Dauriporphine is a monomer extracted from Menispermum dauricum DC, and it exhibits anti-cancer effect in non-small cell lung cancer (NSCLC). The regulatory mechanism of dauriporphine remains incompletely understood, and this study focused on its molecular targets in NSCLC progression. Cell viability, proliferation, apoptosis, invasion, migration, and stemness were evaluated using cell counting kit-8, ethynyl-2'-deoxyuridine assay, flow cytometry, transwell assay, scratch assay, and sphere formation assay, respectively. Bioinformatics analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify targets of dauriporphine in NSCLC. The mRNA and protein expression was quantified using qPCR and Western blot. Co-immunoprecipitation was used to analyze protein interaction and ubiquitination regulation between ubiquitin-specific protease 7 (USP7) and calcium/calmodulin-dependent serine protein kinase (CASK). The role of dauriporphine in vivo was explored using xenograft tumor model. Dauriporphine restrained proliferation, invasion, migration, and stemness of NSCLC cells (p < 0.05). Bioinformatics analysis and WGCNA identified CASK as a core target of dauriporphine in NSCLC. CASK was highly up-regulated in NSCLC samples and cells (p < 0.05). Anti-cancer effects of dauriporphine on NSCLC cells were associated with reduced CASK expression (p < 0.05). USP7 stabilized CASK protein by inducing deubiquitination (p < 0.05). Silencing USP7 restrained NSCLC cell proliferation, metastasis, and stemness by inhibiting CASK (p < 0.05). Dauriporphine interacted with USP7, and then USP7 overexpression reversed the inhibition of dauriporphine in NSCLC cell malignant behaviors (p < 0.05). Dauriporphine reduced tumor growth in vivo and down-regulated USP7 and CASK expression (p < 0.05). This study suggested that dauriporphine blocked the key malignant phenotypes of NSCLC cells via inhibiting USP7-mediated deubiquitination of CASK, thereby promoting its proteasomal degradation. The study elucidates a molecular mechanism underlying anti-tumor role of dauriporphine and providing potential targets for dauriporphine treatment.

Osteosarcoma is the most common primary malignant bone tumor and is associated with a high mortality rate due to its pronounced metastatic potential. Although tricin has been proposed as a chemosensitizer in various malignancies, its anti-metastatic effect in osteosarcoma remains poorly characterized. This study investigated whether tricin suppresses metastasis in human osteosarcoma cells and explored the underlying molecular mechanisms. Our results revealed that tricin significantly inhibited the migration and invasion of U2OS and Saos-2 osteosarcoma cells and downregulated ZNF503 expression at both the mRNA and protein levels. Similarly, siRNA-mediated knockdown of ZNF503 suppressed cell migration, as confirmed by immunofluorescence analysis. Tricin treatment also reduced phosphorylation of PI3K and Akt, without affecting the activation of ERK1/2, JNK1/2, or p38. Additionally, intracellular levels of PIP3 were diminished following tricin exposure. Notably, the Akt activator SC-79 significantly reversed tricin-induced suppression of both ZNF503 expression and cell migration in U2OS and Saos-2 cells. In conclusion, these findings suggest that ZNF503 inhibits osteosarcoma cell motility via the PI3K-PIP3-Akt signaling axis and that tricin exerts anti-metastatic effects by targeting this pathway. Tricin may therefore represent a promising therapeutic agent for inhibiting osteosarcoma metastasis.

In this study, 12 novel sulfonamide derivatives incorporating 2-amino-1,3,4-oxadiazole and 1,3-benzazol-2(3H)-one scaffolds were synthesized and structurally characterized using [1]H NMR, [13]C NMR, and LC-MS analyses. Their inhibitory activities were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase I and II (CA I and CA II), and α-glucosidase. Owing to their potent inhibitory profiles, enzyme kinetic studies were performed to determine inhibition constants (Ki) and inhibition mechanisms. The synthesized compounds exhibited potent nanomolar cholinesterase inhibition. Compound 5b was identified as the most active AChE inhibitor (IC50 = 32.6 ± 2.6 nM; Kᵢ = 7.1 ± 0.6 nM), acting through a competitive inhibition mechanism, whereas compound 5g showed the strongest BChE inhibition (IC50 = 34.6 ± 2.8 nM; Kᵢ = 8.4 ± 0.8 nM) with a mixed-type inhibition profile. The derivatives also displayed significant carbonic anhydrase inhibition, with compound 6d emerging as the most potent inhibitor, particularly against CA II (IC50 = 0.9 ± 0.06 μM; Kᵢ = 0.43 ± 0.037 μM), while exhibiting competitive inhibition and strong activity against both CA isoforms. In contrast, α-glucosidase inhibition was generally weak, with compound 5d showing the highest activity (IC50 = 250.5 ± 21.32 μM). Molecular docking studies revealed favorable binding interactions within the catalytic sites of cholinesterase and carbonic anhydrase enzymes, while 200 ns length molecular dynamics simulations confirmed the stability of representative protein-ligand complexes. In silico ADMET and drug-likeness predictions using SwissADME and pkCSM indicated generally acceptable oral drug-likeness. Compound 6c exhibited the most balanced predicted pharmacokinetic profile, whereas 6d, despite its excellent enzyme inhibition, showed potential limitations associated with higher polarity, limited predicted blood-brain barrier penetration, and predicted toxicity risks. Overall, these findings identify the synthesized sulfonamide derivatives as promising scaffolds for the further development of multifunctional cholinesterase and carbonic anhydrase inhibitors.

Alzheimer's disease requires innovative therapeutic strategies that not only alleviate symptoms but also protect neurons. Donepezil hydrochloride, a cholinesterase inhibitor, and quercetin, a potent antioxidant, were co-formulated into a transethosomal gel to enhance brain delivery and therapeutic efficacy. To design and optimize a Quality by Design (QbD)-based transethosomal gel containing Donepezil hydrochloride and Quercetin, and to establish a stability-indicating, eco-compatible RP-HPLC method for their simultaneous estimation. Chromatographic separation was achieved on a C18 ODS column using an eco-friendly mobile phase of acetonitrile-phosphate buffer (45:55, pH 3.4). Detection was performed at 240 nm, the isoabsorptive wavelength for both drugs. Method validation followed ICH guidelines, and forced degradation studies (acidic, basic, oxidative, thermal, photolytic) were conducted to achieve controlled degradation (5%-20%) while minimizing the use of hazardous solvents. The transethosomal gel was developed using QbD algorithms, optimizing critical parameters including particle size distribution (PDI), zeta potential, entrapment efficiency, and drug release profile. The optimized gel exhibited a vesicle size of 128.4 ± 2.1 nm, PDI of 0.135, zeta potential of +29.52 mV, and 89% and 85% entrapment efficiency of Quercetin and Donepezil HCl. Drug content exceeded 97% for both drugs, while cumulative drug release reached approximately 85%-95% over 10 h. The RP-HPLC method demonstrated excellent linearity (R[2] > 0.995), recovery (98-102%), precision (%RSD < 2%), accuracy, robustness, and an Eco-Scale score of 83.18, confirming excellent analytical greeness. Forced degradation studies confirmed its stability-indicating capability. The study successfully integrates QbD-driven formulation design with a validated eco-friendly RP-HPLC method, providing a robust platform for simultaneous drug delivery in Alzheimer's therapy. This work underscores the synergistic potential of advanced formulation strategies and sustainable analytical validation in translational pharmaceutical research.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which single-target therapies often provide insufficient benefit, motivating the development of multi-target-directed ligands (MTDLs). In this study, a novel series of benzimidazolone-based hybrids incorporating piperazine, coumarin, and triazole moieties was designed, synthesized, and evaluated for inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase-B (MAO-B), as well as antioxidant potential via on-line HPLC-based assays. Structures were confirmed by [1]H-NMR, [13]C-NMR (APT), and elemental analysis. Several compounds showed notable, micromolar-range inhibitory activity, though less potent than the reference drugs. Kinetic analysis showed that the leading compounds inhibited their respective enzymes via a mixed-type mechanism. Compound 1 showed the strongest AChE inhibition (IC50 = 0.777 ± 0.014 µM), compound 9b the highest BChE inhibition (IC50 = 0.659 ± 0.005 µM), and compound 9c the most potent MAO-B inhibition (IC50 = 2.431 ± 0.003 µM). Compound 8a showed the highest CUPRAC copper-reducing capacity, while 7c displayed the strongest DPPH radical-scavenging activity. Liposomal formulations of 4c, 7c, and 8a exhibited enhanced antioxidant responses relative to their free forms. In silico ADME predictions (SwissADME) indicated favorable drug-likeness and blood-brain barrier permeation for the compact scaffold (compound 1) and the piperazine-based hybrids, whereas the larger bis-conjugated derivatives were limited by high polarity and molecular weight. Overall, these benzimidazolone-based hybrids represent promising multi-target candidates for AD drug development.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and excitotoxicity. Ferroptosis and N-methyl-D-aspartate (NMDA) receptor activity,may be interconnected in the pathogenesis of Aβ accumulation and associated neurodegeneration in AD. However, the interplay between these pathways remains poorly understood and underexplored for therapeutic intervention against the AD. The review aims to explore the shared molecular triggers of ferroptosis and NMDA receptor overactivation, including the roles of iron, glutamate overload, calcium dysregulation, and reactive oxygen species (ROS) accumulation. We further highlighted the convergent consequences of these processes on mitochondrial dysfunction, lipid peroxidation, and their impact on Aβ pathology. Particular attention is given to P-glycoprotein (P-gp), an efflux transporter involved in the Aβ clearance at the blood-brain barrier, whose expression and function may be modulated by oxidative stress, iron homeostasis, and NMDA receptor signaling. Emerging evidence indicated that ferroptosis and NMDA receptor activity may disrupt P-gp function, thereby impairing Aβ clearance and promoting its accumulation in the AD. Overall, the review elucidates the molecular mechanisms linking ferroptosis and NMDA receptor overactivation and their impact on P-gp-mediated Aβ transport in the AD, providing integrated mechanisms and harnessing their potential for AD therapeutics.

Aberrant activation of Aurora A kinase causes mitotic spindle assembly, chromosome segregation, and cell cycle progression, leading to genomic instability as well as disruption of several tumor suppressors. Furthermore, ERK has largely emerged as a survival signaling pathway controlling cell proliferation, differentiation, and metastasis. Unfortunately, this pathway is overexpressed in most of the human malignancies. In efforts to develop innovative inhibitors targeting Aurora A/ERK signaling pathway, a novel series of thiadiazolo-, triazolo-pyrimidine hybrids have been designed, synthesized, and assessed for their ability to block Aurora A/ERK and induce apoptosis. Cytotoxicity of the synthesized hybrids was examined against MCF-7, HCT-116 and A549 cell lines. Among the synthesized hybrids, 9a, 9c, and 14b demonstrated higher cytotoxic action than alisertib and GDC-0994 against the MCF-7 and A549 cancer cell lines. IC50 values for these hybrids were 2.59 ± 0.13, 4.63 ± 0.25, and 5.77 ± 0.38, respectively, against MCF-7 cell line and were 3.61 ± 0.19, 3.85 ± 0.21, and 4.23 ± 0.15, respectively, against A549. The selected hybrids significantly suppressed p-Aurora A kinase level as well as p-ERK1/2 level and its upstream regulators p-SRC, p-c-RAF, p-MEK1/2; meanwhile, ERK downstream effectors FOXO3a level was upregulated, and c-Myc was downregulated, in a dose-dependent manner. The selected hybrids significantly decreased the expression of Bcl-2 protein while increasing the levels of p53, caspase-7, caspase-9, and Bax. They effectively induced pre-G1 phase, G0/G1 phase apoptosis, and G2/M phase arrest. The synthesized hybrids possessed favorable binding interactions in the molecular docking investigations as well as appropriate drug-like characteristics.

Tumor drug resistance and metastasis are leading causes of cancer‑related mortality, both of which are tightly governed by multiple signaling pathways. The AKT‑GSK‑3β axis is a critical regulator of tumor progression, mediating drug resistance and epithelial‑mesenchymal transition (EMT) through its downstream targets. Aberrantly activated AKT‑GSK‑3β signaling modulates the expression and degradation of the drug efflux pump P-gp, which expels chemotherapeutic agents, including paclitaxel (PTX), from cancer cells, resulting in chemotherapy failure and drug resistance. Moreover, hyperactivated AKT‑GSK‑3β signaling drives EMT, a key process closely linked to tumor metastasis and malignant progression. Dioscin (Dio), a natural steroidal saponin, exhibits significant anti‑tumor activity in multiple cancers. However, whether Dio reverses chemoresistance and inhibits tumor growth by targeting the AKT‑GSK‑3β pathway to promote P-gp degradation and suppress EMT remains elusive, which is the central focus of this study. To explore whether Dio enhances the sensitivity of drug-resistant cancer cells to PTX and inhibits cancer metastasis and the EMT process, as well as its potential mechanism(s). Paclitaxel-resistant TE-1/PTX and HeLa/PTX cells were subjected to SRB, colony formation, Rh123 accumulation, wound-healing, and Transwell assays to evaluate Dio's chemosensitizing, anti-EMT, and anti-metastatic effects. Network pharmacology, molecular docking, CETSA, and proteolysis assays verified a direct Dio-AKT1 interaction. Western blotting, Co-IP, and MG132 and MK2206 rescue experiments clarified AKT/GSK3β-dependent P-gp ubiquitin-proteasomal degradation and EMT suppression. HeLa/PTX xenograft models were generated; H&E staining and immunoblotting were used to assess tumor growth, biosafety, and intratumoral protein profiles for in vivo validation. Dio sensitized PTX-resistant cells to paclitaxel, increased intracellular Rh123 accumulation, and inhibited cell migration and invasion. Mechanistically, Dio directly bound AKT1 to suppress AKT/GSK3β signaling, promoted ubiquitin-proteasomal degradation of P-gp, and reversed EMT by upregulating epithelial markers and repressing mesenchymal markers and EMT transcription factors. In vivo, Dio restrained xenograft tumor growth with negligible systemic toxicity, and intratumoral expression patterns of AKT/GSK3β, P-gp, and EMT-related proteins mirrored in vitro findings. Dio has the potential to be a safe and effective agent for drug-resistant cancer therapy.

MDR ESKAPE pathogens are the leading cause of hospital-acquired infections (HAIs) that resist most antibiotics and form biofilms. Biofilm formation is dependent on the two-component system (TCS), which regulates virulence traits including adhesion to host tissues, evasion of innate immunity, the synthesis of exopolysaccharides, and antibiotic resistance. TCS sense environmental stimuli such as pH, osmotic pressure and antimicrobial peptides. They regulate gene expression to promote bacterial survival and persistence during infection. TCS represents a contemporary and novel pathway for the advancement of targeted, adjuvant-based options to fend off infections caused by ESKAPE pathogens. Targeting TCS may improve drug penetration and reduce resistance pressure, although challenges remain due to their structural conservation, regulatory complexity, and mutation-driven resistance. However, there are several limitations in targeting TCS for drug development like TCS not always being essential for bacterial viability, structural homologies between TCS are not sufficient for broad-spectrum inhibitors, sometimes TCS can be involved in complex and essential regulatory networks and can evolve resistance mechanisms by mutations. To further investigate this paradox, we implemented comprehensive computational and phylogenetic analyses of selected ESKAPE TCS. The findings from this investigation form the basis for our in-depth review of the significance and challenges of TCS as emerging drug targets.

Diabetes mellitus (DM) related erectile dysfunction (ED) is a common complication in males. We aim to explore the specific regulatory mechanisms of TEA domain family member 1 (TEAD1) in DMED rats. Diabetic ED in rats was induced by streptozotocin and evaluated by the intracavernosal pressure response to electrical stimulation and the apomorphine test. Corpus cavernosum smooth muscle cells (CCSMCs) were isolated to explore the role of TEAD1 in phenotypic transformation. TEAD1 knockdown was performed in DMED rats and CCSMCs using the CRISPR/Cas9 technology. Hematoxylin-Eosin and Masson staining were applied to observe the penile tissue pathology. The CCSMC function was evaluated by detecting viability and apoptosis. Protein and gene expression levels were examined by Western blot and real-time quantitative polymerase chain reaction. The TEAD1 gene knockdown ameliorated erectile function in DMED rats. Knockdown of TEAD1 in CCSMCs of DMED rats enhanced their viability and inhibited their apoptosis, promoting the transformation of CCSMCs from a synthetic to a contractile phenotype. Furthermore, bioinformatics analysis identified the calcium signaling pathway as a candidate pathway warranting further experimental investigation. TEAD1 knockdown was associated with altered expression of calcium-related proteins and elevated intracellular Ca[2+] levels. The calcium channel blocker Nimodipine could reverse the improvement of erectile function in DMED rats and the transformation of CCSMC phenotype caused by TEAD1 knockdown. TEAD1 knockdown promotes the transformation of CCSMCs from a synthetic to a contractile phenotype and is associated with modulation of calcium signaling-mediated contractile machinery, contributing to the relief of DMED.