Podophyllotoxin (PTOX), a plant-derived aryltetralin lignan, has long been appreciated for its strong cytotoxic and antimitotic properties. Various derivatives of PTOX, including etoposide and teniposide, are well-established chemotherapeutics, although their use is largely hampered by systemic toxicity, low solubility, and drug resistance. Recent developments in modern chemistry and cancer biology have led to growing interest in developing novel PTOX-derived compounds with improved efficacy and reduced toxicity. This review presents the molecular mechanisms underlying the antitumor activity of PTOX and its derivatives, with particular emphasis on the inhibition of tubulin polymerization and DNA topoisomerase II. Furthermore, the roles of key signaling pathways, including PI3K/AKT, NF-κB, AMPK/HIF-1α, and Chk2/Twist1/EMT, in mediating antitumor effects in breast, lung, liver, and colorectal cancers are highlighted. Recent strategies involving the incorporation of PTOX into nanoparticles, hybrid molecules, and other bioactive systems have expanded its therapeutic potential by improving solubility, pharmacokinetics, and tumor selectivity. Overall, understanding structural modifications and molecular interactions of PTOX derivatives provides a strong foundation for the rational design of more potent and targeted anticancer agents.

The precise inhibition of CD47-SIRPα interaction to promote macrophage phagocytosis and thereby mobilize the immune microenvironment is an essential strategy in lung cancer immunotherapy. Herein, we explored the role of Teniposide (Ten/VM-26) in the CD47-SIRPα interactions and macrophage phagocytosis, with insights into the target and molecular mechanism. Ten/VM-26 demonstrated not only chemotherapeutic but also immunostimulatory effects in lung cancer models. Macrophage depletion attenuated the immune activation induced by Ten, which was associated with enhanced phagocytosis, cGAS-STING signaling, and M1 polarization of macrophages. Our data indicated that Ten suppressed CD47 and thereby dampened the interaction between CD47 and SIRPα, which are highly expressed in lung cancer cells and macrophages respectively. Conversely, CD47 supplementation impaired Ten-driven phagocytosis and M1 polarization of macrophages. Further data suggested that Ten bound to TRIM54, which may be involved in CD47 ubiquitination and degradation. To summarize, our findings suggest that Ten down-regulates CD47 through its binding to both CD47 and TRIM54, thereby disrupting the CD47-SIRPα interaction, enhancing macrophage phagocytosis, cGAS-STING activation, and promoting M1 polarization, supporting the potential of targeting CD47 for lung cancer immunotherapy.

Lignans constitute a diverse family of plant metabolites with therapeutic potential. Among them, podophyllotoxin-type aryltetralin lignans serve as precursors for etoposide and teniposide. Etoposide is an essential anticancer medicine approved for first-line treatment of small cell lung cancer, whereas teniposide is used for treatment of leukemia and some brain tumors. Currently, these drugs depend on extraction of precursors from the endangered plant Sinopodophyllum hexandrum, followed by chemical transformations. By identifying key glycosyltransferases and executing more than 60 genetic edits involving 45 heterologous enzymes, the complex biosynthetic pathway of podophyllotoxin-type lignans was reconstructed in yeast. In this study, we established a chemoenzymatic route that streamlines the synthesis of etoposide and teniposide through a single chemical step from biosynthetic precursor 4'-demethyl-epipodophyllotoxin-4-O-glucoside, which enables a secure supply chain of these essential medicines.

Ataxia-Telangiectasia (AT) is a rare disorder characterized by ATM deficiency and mitochondrial dysfunction. Because SIRT3 contributes to mitochondrial homeostasis in ATM-deficient settings, it represents a relevant molecular context for repurposing-oriented target-engagement studies. Here, we present an integrated computational and biophysical workflow designed to identify experimentally tractable SIRT3 binders within a clinically approved chemical space. A curated dataset of 2342 FDA-approved drugs was screened using hierarchical GNINA-based virtual screening, SAveRUNNER network analysis, triplicate 300 ns molecular dynamics simulations, post-MD redocking, MM/PBSA calculations, and experimental SPR validation. Four compounds were prioritized for further investigation: binimetinib, olaparib, mizolastine, and teniposide. Surface plasmon resonance (SPR) demonstrated direct binding of all four compounds to recombinant SIRT3, with equilibrium dissociation constants in the nano- to low-micromolar range. Binimetinib showed the highest apparent affinity (KD = 21.28 ± 3.5 nM), followed by olaparib (84 ± 5.7 nM), mizolastine (138 ± 3.5 nM), and teniposide (1470 ± 58 nM). Computational analyses supported the compatibility of these ligands with dynamically relaxed SIRT3 binding-site conformations and enabled the efficient prioritization of experimentally validated binders. These results support the value of an integrated in silico/SPR pipeline for identifying SIRT3-binding scaffolds. However, the functional consequences of binding, isoform selectivity, and biological relevance in ATM-deficient disease models remain to be established.

Hemophagocytic lymphohistiocytosis (HLH), a severe, life-threatening hyperinflammatory syndrome driven by dysregulated immune activation, is characterized by rapid clinical deterioration and poor outcomes that pose critical challenges for clinical management. Here, we report on a female patient aged 10 years and 3 months who was diagnosed with systemic lupus erythematosus (SLE)-associated hemophagocytic lymphohistiocytosis with central nervous system (CNS) involvement. Treatment with the conventional HLH-94/2004 regimen failed to control disease progression. Subsequently, second-line salvage therapy, consisting of emapalumab in combination with teniposide and dexamethasone, was initiated to account for the CNS involvement. The patient achieved sustained, complete clinical response following use of this modified therapeutic approach. Our findings suggest that this combination regimen may offer a potentially feasible therapeutic alternative for managing patients with SLE-associated HLH accompanied by CNS involvement; however, given the single-case nature of this report, further validation in larger cohorts is needed.

Podophyllotoxin has significant anti-tumour, anti-condyloma and anti-HIV characteristics, and its derivatives, such as etoposide (VP 16-213), teniposide (VM-26) and Etopophos, have been approved in the market by the US FDA and are widely used in the clinical treatment of various cancers, such as lymphoma, lung cancer and acute leukaemia. Podophyllotoxin is currently extracted primarily from certain species of the Podophyllum genus (e.g., P. hexandrum and P. peltatum), while excessive harvesting of these wild resources has led to their progressive depletion. Podophyllotoxin can be obtained by chemical synthesis, semi-synthesis or tissue culture, but the high production cost, low yield and environmental pollution greatly limit its large-scale production and application. In this study, an endophytic fungus 25[#] putatively producing podophyllotoxin was obtained from the rhizomes of an endangered medicinal plant Dysosma versipellis. Based on multi-gene phylogenetic analyses (including tef1, tub2, rpb2, and cmdA sequence data) and morphological characteristics, the strain was identified as Fusarium odoratissimum. By using HPLC and UPLC-QTOF-MS/MS, the isolate was found to produce a compound putatively identified as podophyllotoxin, with an estimated yield of 269.0 µg·g[- 1] (dry mycelial weight). Biological evaluation revealed that the mycelial methanolic extract possessed antibacterial activity against Staphylococcus aureus, Escherichia coli, and Micrococcus luteus, with inhibition zones of 13.1, 16.3, and 17.1 mm, respectively. Furthermore, the mycelial ethyl acetate extract exhibited measurable cytotoxic activity against the HepG2 cell line (IC50 = 32.58 ± 1.61 µg·mL[- 1]). Quantitative correlation analysis suggested that the estimated PTOX-equivalent concentration in the crude extract was in reasonable agreement with the IC50 of the pure PTOX standard, indicating that F. odoratissimum 25[#] may represent a potential natural source of a compound putatively identified as podophyllotoxin.

Understanding how environmental conditions alter the mechanical stability of drug-target interactions is essential for developing robust antiviral therapeutics. Here, we investigate the pH-dependent mechanical response of the SARS-CoV-2 main protease (Mpro) when bound to two herbal inhibitors (Gallocatechin gallate and Glabridin) and two synthetic compounds (Remdesivir and Teniposide) using steered molecular dynamics (SMD) simulations. Protonation states reflecting acidic endosomal conditions were assigned using PROPKA, and mechanical resilience was quantified through rupture forces and pulling work during forced unbinding. The results reveal two distinct pH-dependent behaviors: acidic environments strengthen the mechanical stability of Mpro-Remdesivir and Mpro-Glabridin complexes, whereas Gallocatechin gallate and Teniposide exhibit significantly reduced rupture forces and pulling work. Among the tested compounds, Gallocatechin gallate displays the highest mechanical stability at neutral pH, whereas Remdesivir demonstrates superior resistance to forced unbinding under acidic conditions. Mechanistic analysis reveals that protonation of catalytic residues His41 and Glu166 reshapes hydrogen-bond networks and electrostatic interactions, explaining the ligand-specific responses. These findings demonstrate that environmental pH can invert inhibitor performance rankings, with rupture forces spanning ∼120-850 pN across ligands and exhibiting pronounced pH-dependent shifts, including a decrease for Gallocatechin gallate (∼800 to ∼600 pN) and a substantial increase for Glabridin (∼120 to ∼450 pN), highlighting the importance of incorporating mechanical metrics and pH variability into antiviral therapeutic development for physiologically variable microenvironments.

[This corrects the article DOI: 10.3389/fonc.2026.1784250.].

Diffuse midline glioma with H3K27M mutation (H3K27M-mutant DMG) is a rare central nervous system tumor with an extremely poor prognosis. The absence of a standard treatment regimen makes achieving durable survival benefits a major therapeutic challenge. This study reports the case of a 17-year-old male diagnosed with H3K27M-mutant glioma. Following surgical resection and postoperative concurrent chemoradiotherapy, the patient received adjuvant therapy combining teniposide (VM-26) and bevacizumab, which led to significant radiological and symptomatic improvement. By examining the efficacy of this individualized comprehensive strategy-integrating surgery, chemoradiotherapy, and targeted therapy with teniposide-we assess its potential mechanisms and clinical value. This case suggests a potentially effective treatment option for patients with H3K27M-mutant DMG.

Purinergic receptor (P2X7R), an adenosine triphosphate (ATP) gated nonselective cation channel, is an emerging target for several neurodegenerative conditions, including retinal degeneration. In particular, P2X7R has an established role in multiple inflammatory and immune responses, being implicated in the formation and activation of NLRP3 inflammasome leading to inflammatory priming and release of immune cytokines. Despite several efforts in P2X7R antagonist design, no drugs have reached the market yet. In this perspective, through an integrated in silico and in vitro approach, we aimed to repurpose FDA approved drugs in search of novel safe treatments for retinal degenerative diseases, where P2X7R has been found to play a detrimental role. Virtual screening of about 10,000 FDA approved drugs identified 6 putative P2X7 antagonists. Three out of these six compounds inhibited hP2X7, but not rat receptors, while only one compound, tipranavir, inhibited also mouse P2X7R. Then, for these three P2X7R antagonists, namely bazedoxifene, teniposide and tipranavir, we have evaluated the in vitro tolerability by treating immortalized human Müller cells (MIO-M1), primary retinal endothelial cells (HRECs), human umbilical vein endothelial cells (HUVECs) and human retinal pigmented epithelial cells (hRPEs). Tipranavir and teniposide were well tolerated by the mentioned retinal cells, thereby they have been further evaluated in in vitro models of glaucoma, diabetic retinopathy, and age-related macular degeneration. Tipranavir and teniposide showed retinal cell protection, modulating the expression of HIF-1α, VEGF-A, and inflammatory cytokines. Therefore, these compounds are worthy of further investigation to manage retinal degenerative conditions.

High expression of Lysine-Specific Demethylase 5B (KDM5B) in lung cancer drives tumorigenesis and immunosuppression. KDM5B is negatively correlated with endoplasmic reticulum (ER)-phagy receptors such as TEX264, indicating that selective induction of ER-phagy may degrade KDM5B. Our work revealed that chemotherapeutic drug Teniposide (Ten) was a potent anti-lung cancer agent, which could increase the stability of TEX264. The present study aims to elucidate the critical target and mechanism by which Ten inhibits KDM5B through TEX264-associated ER-phagy against lung cancer. Ten exhibited potent lung cancer suppression ability, as evidenced by the weakened proliferation of organoids and tumor grafts in mice along with activation of the immune microenvironment. Highly-expressed KDM5B demonstrated down-regulation upon Ten treatment, which may be attributed to its degradation via ER-phagy. Blockage of ER-phagy weakened Ten-mediated KDM5B degradation. Insightful investigations discovered that Ten activated OTUD3, a deubiquitylase, which stabilized TEX264, a crucial receptor for ER-phagy. Notably, genetic knockdown of TOP2A impacted little on the Ten-mediated ER-phagy. OTUD3 silencing dampened Ten-driven ER-phagy and KDM5B inhibition. To summarize, these findings demonstrate that Ten effectively inhibits lung cancer and activates immunocytes by KDM5B inhibition, which is regulated by TEX264-associated ER-phagy. Most importantly, OTUD3 serves as an essential target for enhancement of TEX264 stabilization.

Biological databases play a crucial role in life sciences research by organizing vast amounts of data, enabling efficient access and analysis. Numerous databases have been published across various research areas, yet there remains a need for updated platforms in the field of molecular docking and molecular dynamics simulation research. To address this gap, we have developed an extensive and user-friendly platform focused on compiling the binding energies of compounds associated with a wide range of biological activities. The database offers free access to data on 1321 compounds, including abstracts, references, isomeric SMILES, and 22 molecular properties. Researchers can also securely store their docking and screening data. To demonstrate its capabilities, molecular docking was performed on the top 10 compounds with the best binding energies against human metapneumovirus (HMPV) using AutoDock Vina and the crystal structure (PDB ID: 8FPJ). MK-3207 and Etoposide exhibited docking scores of -10.3 and -9.6, respectively. The top two compounds were further selected for MD simulations, confirming stable binding interactions with the viral protein. Additional compounds, including Teniposide, UK432097, 85019940, Setileuton, Orvepitan, Cep-11981, Tadalafil, and VS-5584, were also analyzed, providing further insights into their binding mechanisms and potential therapeutic relevance. The database is developed using PHP, HTML, CSS, JavaScript, and Python and is freely accessible at https://www.pbed.habdsk.org/.

The study investigated Dactylonectria torresensis as a sustainable source of podophyllotoxin (PTOX), a key precursor for anticancer drugs such as etoposide and teniposide. The fungus was identified through morphological analysis and ITS rDNA sequencing. PTOX from the fungal extract was isolated and characterized using high-performance liquid chromatography, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. Antioxidant activity was evaluated via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and reducing power assays, showing comparable 50% inhibition (IC50) values for standard and fungal PTOX - 297.4 versus 309.8 µg/mL (DPPH) and 306.6 versus 316.3 µg/mL (reducing power). Cytotoxicity against MCF-7 breast cancer cells also revealed similar IC50 values: 3.083 µM for standard and 3.188 µM for fungal PTOX. PTOX production was optimized through a two-phase statistical approach: Plackett-Burman Design followed by Face-Centered Central Composite Design. Initially, D. torresensis produced 78.46 µg/g dry weight (DW) of PTOX, which increased 6.35-fold to 498.76 µg/g DW after optimization.

Lignans exhibit a wide range of useful bioactivities. A key intermediate in their biosynthesis in plants is (-)-pluviatolide, which directs the pathway towards various high-value lignans like (-)-podophyllotoxin - the precursor of the clinically relevant antitumor drugs etoposide and teniposide. In an attempt to develop more sustainable ways for the production of lignans, which are traditionally isolated from plants, we previously established a heterologous biosynthesis of (-)-pluviatolide in Escherichia coli, in which recombinant genes were expressed from multiple plasmids. In this study, the genes encoding the four-enzyme, four-step reaction cascade from (+)-pinoresinol to (-)-pluviatolide were integrated into the chromosome of E. coli C41(DE3). The plasmid-based and plasmid-free E. coli strains were compared in resting and growing cell approaches. The performance of the plasmid-free recombinant system was similar to that of the plasmid-based system, regardless of the approach tested. The addition of glycerol and glucose as energy and carbon sources enhanced the productivity towards (-)-pluviatolide. LC-MS analysis revealed complete conversion of the substrate (+)-pinoresinol and the formation of (-)-pluviatolide with 99% product ratio in resting cells and 92% in growing cells.

The STimulator of Interferon Genes (STING) is a key adaptor protein in the innate immune response to cytosolic DNA, making it a promising therapeutic target. Identifying novel STING ligands could provide new opportunities for immune modulation.