Drug Database
PO

podophyllotoxin (Warticon Cream / Warix / Warticon)

✓ Approved

Rottapharm Madaus · therapeutic agent

What is podophyllotoxin?

podophyllotoxin is a therapeutic agent developed by Rottapharm Madaus. It is approved for therapeutic indications via topical.

Drug Profile

Brand NamesWarticon Cream, Warix, Warticon
CompanyRottapharm Madaus
RouteTopical
StatusApproved
Sources: ClinicalTrials.gov, Rottapharm Madaus

Therapeutic Indications

podophyllotoxin is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Infections and infestationsPapilloma viral infection✓ Approved

Related Research Articles

PubMedBiochemical pharmacology2026-10-06

Chemical proteomics and phenotypic profiling identify αFOD as a podophyllotoxin-derived PGK1 inhibitor that suppresses glycolysis and proliferation in hepatocellular carcinoma.

Liu Run-Hua RH, Chen Xi X, Li Hong-Mei HM, Zhao Wei W et al.

HCC remains one leading cause of cancer-related mortality worldwide, but effective systemic therapeutic options are limited. PGK1 has emerged as a promising therapeutic target in HCC, yet PGK1 inhibitors with anti-HCC activity are rarely reported. This study was sought to identify the target of a novel podophyllotoxin derivative αFOD and evaluate its anti-HCC efficacy, glycolytic inhibition, and preliminary safety profile. αFOD preferentially inhibited tumor cells over non-malignant cells and displayed potent activity against HCC cell lines, with IC50 of 0.80 ± 0.18  μM in HepG2, 2.57 ± 0.75  μM in Huh7, and 1.82 ± 1.04  μM in SNU-387 cells. In two HCC patient-derived organoids, αFOD exhibited IC50 of 8.76 ± 0.79 and 3.70 ± 0.25  μM, with efficacy comparable to that of oxaliplatin and lenvatinib and superior over that of etoposide. Using chemical proteomics and phenotypic profiling, we identified PGK1 as a target of αFOD. Surface plasmon resonance assays revealed a Kd of 11.50  μM, and molecular interaction analyses based on our in-house apo-PGK1 crystal structure predicted that αFOD occupies the 3-phosphoglycerate-binding pocket of PGK1 through interactions with Arg38, Arg65, Thr167, and Ala376. In consistency with target engagement, αFOD inhibited PGK1 enzymatic activity and suppressed glycolytic flux in HepG2 cells. In a HepG2 xenograft model, αFOD inhibited 66.7% tumor growth and outperformed etoposide while exhibiting reduced systemic toxicity compared to oxaliplatin. Collectively, these findings establish αFOD as a podophyllotoxin-derived PGK1 inhibitor that suppresses glycolysis and HCC proliferation, supporting the rational development of Podophyllum-derived scaffolds and highlighting PGK1 inhibition as a promising therapeutic strategy for HCC.

PMID 42838236
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PubMedDrug design, development and therapy2026-09-27

Artesunate Targets MBL2 to Modulate the TLR4/NRF2/HO‑1 Axis and Ameliorate Podophyllotoxin‑Induced Liver Injury.

Wei Mingyue M, He Junjie J, Zhang Yanzhao Y, Chen Hetao H et al.

Drug-induced liver injury (DILI) presents a significant clinical challenge with limited preventive and therapeutic options. Artesunate (ART) holds potential for DILI treatment; however, its precise hepatoprotective mechanisms and direct molecular target(s) remain unclear. We evaluated ART in a podophyllotoxin (PPT)-induced rat model of DILI. Its direct target was identified through integrated chemical proteomics (pull-down/LC-MS/MS) followed by biophysical validation (SPR, MST) and molecular dynamics simulations. Mechanistic insights from hepatic transcriptomics (RNA-seq) were confirmed by Western blot, and extended with targeted metabolomics and 16S rRNA sequencing of gut microbiota. ART administration conferred significant hepatoprotection in the PPT-induced rat model, as evidenced by dose-dependent amelioration of key serum markers of liver injury (P < 0.05), attenuation of hepatic oxidative stress, and improved histopathological outcomes. Mechanistically, we identified mannose-binding lectin 2 (MBL2) as a direct, high-affinity target of ART (KD ≈ 3.84 µM). Upon binding to MBL2, ART suppressed the hepatic TLR4/NF-κB inflammatory axis and, in parallel, relieved NF-κB-mediated repression of NRF2, thereby cooperatively activating the NRF2-driven antioxidant defense program. Integrated multi-omics analysis further revealed that ART remodeled the gut microbiota, enriching beneficial genera including Lactobacillus, and that the abundance of these bacteria correlated positively with hepatic levels of antioxidant metabolites (P < 0.05), supporting a functional role of the gut-liver axis in its systemic protective effects. This study elucidates that ART alleviates DILI through targeting MBL2, thereby dually modulating the NF-κB/NRF2 signaling axis to simultaneously suppress inflammatory responses and enhance endogenous antioxidant defenses. These findings provide a novel and robust pharmacological basis for repositioning ART for the clinical prevention and treatment of DILI.

PMID 42799208
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PubMedMini reviews in medicinal chemistry2026-09-20

Podophyllotoxin Derivatives in Oncology: Mechanistic Insights, Therapeutic Applications, and Future Directions.

Soni Sakshi S, Rathee Sunny S, Patil Umesh K UK

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.

PMID 42763930
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PubMedDrug metabolism and disposition: the biological fate of chemicals2026-09-18

Liquid chromatography-high-resolution mass spectrometry-based integrated strategy combining in silico prediction and molecular networking for metabolite identification of podophyllotoxin in a fatal poisoning case.

Wu Mengyi M, Feng Jialin J, Zhao Junbo J, Qiang Huosheng H et al.

Podophyllotoxin is an aryltetralin lignan with potent antimitotic and antiviral activities; however, its severe toxicity restricts clinical use to topical application, and systemic exposure to it can result in life-threatening poisoning. However, its metabolic profile remains largely uncharacterized, leaving a critical gap in the biomarkers available for confirming intoxication. Here, we used an integrated nontargeted screening strategy to investigate podophyllotoxin metabolism in post-mortem blood from a rare fatal case of podophyllotoxin poisoning. Two complementary nontargeted screening strategies were established using liquid chromatography coupled to high-resolution tandem mass spectrometry data acquired in both positive and negative ion modes. SyGMa was first used to generate a predicted metabolite list of podophyllotoxin, enabling target analysis against the acquired data. Subsequently, molecular networking was applied to cluster structurally related compounds across specimens based on high-resolution tandem mass spectrometry spectral similarity, enabling visualization and discovery of unknown metabolites and their structural relationships. By integrating these approaches, a total of 11 potential metabolites were identified, including 2 phase Ⅰ metabolites and 9 phase Ⅱ metabolites, of which 5 were previously unreported. Among these, the O-demethylenated and methylated products (m/z 416.1471) are proposed as potential biomarkers for assessing podophyllotoxin exposure. The integrated workflow demonstrated herein facilitates xenobiotic metabolite identification in biological samples, and the characterized metabolites may support future metabolite annotation and exposure assessment through incorporation into mass spectral libraries. SIGNIFICANCE STATEMENT: Human metabolic data for podophyllotoxin remain scarce despite the severe toxicity associated with systemic exposure. By analyzing post-mortem blood from a fatal poisoning case, this study expands knowledge of podophyllotoxin biotransformation and proposes previously unreported metabolites. The results further demonstrate the complementary value of combining in silico prediction with molecular networking for metabolite discovery and annotation, highlighting a practical strategy for characterizing xenobiotic metabolites in limited biological specimens.

PMID 42759206
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PubMedPlants (Basel, Switzerland)2026-09-15

Elicitor-Mediated Enhancement of Secondary-Metabolite Biosynthesis in Juniperus (Cupressaceae): Current Advances and Future Perspectives.

Orken Aisulu A, Tussipkan Dilnur D, Manabayeva Shuga A SA

Juniperus species are a rich source of pharmacologically important secondary metabolites, including terpenoids, lignans, flavonoids, and phenolic compounds. However, the commercial utilization of these metabolites is limited by the plant's slow growth, poor natural regeneration, and environmental variability affecting metabolite accumulation. Integrating plant tissue culture with elicitation strategies is a promising approach for sustainably producing these valuable compounds. This review summarizes the diversity, biological activities, and biotechnological significance of secondary metabolites in Juniperus, focusing on tissue culture systems and enhancement of metabolite biosynthesis through elicitors. It critically evaluates the current knowledge of the effects of signaling compounds such as methyl jasmonate (MeJA), jasmonic acid (JA), and salicylic acid (SA), as well as other abiotic and biotic elicitors including silver nanoparticles (AgNPs), chitosan, and chito-oligosaccharides. Particular attention is given to their effects on podophyllotoxin, phenolic, flavonoid, and other bioactive metabolite accumulation. Elicitation responses appear to depend strongly on species, culture system, elicitor type, and treatment conditions. This review also highlights major knowledge gaps, particularly the limited understanding of the regulatory mechanisms controlling secondary-metabolite biosynthesis in Juniperus species. Overall, the available evidence suggests that integrating optimized elicitation strategies with transcriptomics, metabolomics, and metabolic engineering could improve our understanding of secondary metabolite regulation and facilitate the development of sustainable Juniperus tissue culture platforms for producing high-value natural products.

PMID 42739361
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PubMedFrontiers in microbiology2026-09-02

Fungal colonization and candidate metabolite-mediated toxicity of Fusarium solani KMZW-1 against adult Bactrocera dorsalis.

Li Huiqin H, Zhao Zhiyi Z, Wu Mingqi M, Shi Chunlan C et al.

This study examined the interaction between Fusarium solani KMZW-1 and adult Bactrocera dorsalis, with emphasis on cuticular colonization, adult-stage pathological effects, and candidate metabolite-mediated toxicity. KMZW-1 showed Fusarium-like colony and conidial morphology and colonized mainly tarsal setae, joints, and recessed cuticular regions, where fungal conidia and hyphae progressively accumulated over time. Fungal treatment reduced adult survival in a concentration-dependent manner (P < 0.001) and lowered egg production per female, likely due to reduced male survival and fewer mating opportunities, whereas egg hatchability, larval pupation, and adult emergence of offspring were not significantly affected (P > 0.05). Untargeted LC-MS/MS profiling annotated 3073 metabolites, and candidate secondary metabolites were prioritized using pathway assignment, CAS-confirmed identity, normalized peak-area abundance, reported biological activity and commercial availability. Among coumarin, umbelliferone and podophyllotoxin, podophyllotoxin showed the lowest 24 h LC50 values against adult flies, at 24.33 μg mL-1 for females and 21.03 μg mL-1 for males. These results indicate that KMZW-1 produces a reproducible surface-colonization-associated adult-stage phenotype in B. dorsalis. Podophyllotoxin should be interpreted as a prioritized candidate with confirmed topical toxicity, not as a confirmed in vivo virulence determinant. Further work is required to confirm metabolite identity with authentic standards, quantify metabolite production during infection, determine internal invasion dynamics, and evaluate mode of action and non-target safety.

PMID 42682651
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