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Abstract

Prostate cancer remains one of the leading causes of cancer-related mortality among men worldwide. Although several treatment strategies are available, their clinical effectiveness is often limited by problems such as androgen resistance, adverse side effects, and frequent disease recurrence. In recent years, herbal bioactive compounds have attracted considerable attention because of their low toxicity and ability to act on multiple molecular targets. Exploring the molecular basis of their anticancer activity is important for identifying new therapeutic candidates and supporting translational research. This review aims to critically examine the therapeutic relevance of herbal bioactives against prostate cancer, with particular emphasis on their molecular mechanisms and network pharmacology-based evidence. Relevant literature was collected from databases including PubMed, Scopus, Web of Science, Google Scholar, TCMSP, and IMPPAT up to 2025.Studies were screened according to PRISMA guidelines, and only articles reporting molecular targets, pathway mechanisms, docking, or network pharmacology insights were included. The analysis highlights several phytochemicals—such as quercetin, kaempferol, curcumin, resveratrol, ellagic acid, berberine, and epigallocatechin gallate—that regulate key oncogenic pathways. Frequently modulated molecular targets include AKT1, AR, TP53, CASP3, STAT3, and BCL2, while enriched pathways involve PI3K–Akt, apoptosis, androgen receptor signaling, and cell-cycle regulation. Network pharmacology and docking studies demonstrate strong binding affinities and multi-node regulatory capacity of these bioactives, supporting their therapeutic promise. In conclusion, herbal bioactives offer substantial potential for the development of multi-target therapeutics against prostate cancer. Future research should emphasize mechanistic validation, Nano-formulations for targeted delivery, and well-designed clinical trials to accelerate translation into clinical practice

Keywords

Prostate cancer; Herbal bioactives; Network pharmacology; Molecular mechanisms; Signaling pathways; Docking; Phytochemicals; Drug discovery

Introduction

Among male malignancies, prostate cancer remains a major global health burden due to its high incidence and disease-associated mortality.(1). Prostate cancer cases have gone up steadily over the past two decades, driven by demographic aging, sedentary lifestyles, unfavorable dietary patterns, and the broader implementation of improved screening and diagnostic strategies. (2). Although early-stage prostate cancer is frequently managed successfully with surgery, radiotherapy, or androgen deprivation therapyA significant number of people eventually develop castration-resistant prostate cancer (CRPC), an advanced and aggressive illness with a dismal prognosis and few treatment choices. (3). The need for new and safer treatment approaches is highlighted by the development of drug resistance, unfavorable side effects, and relapse after traditional chemotherapy treatments. (4). The need for new and safer treatment approaches is highlighted by the development of drug resistance, unfavorable side effects, and relapse after traditional chemotherapy treatments.

Plants and their bioactive metabolites have long been integral to traditional medicinal practices and continue to represent a significant source of modern pharmaceutical compounds. (5). Many bioactives have demonstrated antiproliferative, antioxidant, anti-inflammatory, and pro-apoptotic properties across diverse cancer types, including prostate cancer (6). Unlike conventional drugs that are designed to interact with a single target, herbal bioactive compounds typically modulate numerous receptors, enzymes, transcription factors, and signalling pathways simultaneously(7). This polypharmacological behavior is particularly relevant to prostate cancer, a disease that involves complex molecular networks regulating cell proliferation, angiogenesis, metastasis, apoptosis, and immune evasion(8). Several phytochemical classes—including flavonoids, lignans, alkaloids, terpenoids, saponins, phenolic acids, and stilbenes—have shown promising anticancer potential in experimental models of prostate cancer (9).

In vitro studies have identified numerous compounds capable of suppressing tumor cell viability, inhibiting migration and invasion, inducing apoptosis, and modulating oxidative stress in prostate cancer cell lines such as PC-3, DU145, LNCaP, and 22Rv1(10). Among the most well-studied bioactives are quercetin, kaempferol, curcumin, epigallocatechin gallate (EGCG), berberine, resveratrol, and ursolic acid(11). These compounds influence central molecular targets and signalling pathways including AR, PI3K–Akt, MAPK/ERK, NF-κB, Wnt/β-catenin, mTOR, and apoptotic regulators such as BAX, BCL-2, and CASP3(12) . Beyond individual mechanisms, many herbal bioactives have been shown to regulate epithelial–mesenchymal transition (EMT), angiogenesis through VEGF inhibition, inflammation through COX-2 and IL-6 suppression, and metabolic reprogramming in prostate cancer cells (13).

Despite a growing body of evidence, the exact mechanisms through which herbal compounds exert therapeutic effects remain incompletely understood. Most experimental studies describe outcomes isolated to single targets or pathways, overlooking the interconnected nature of cancer signalling networks (14). Network pharmacology has become a potent strategy in natural-product-based drug discovery to overcome this restriction. Network pharmacology maps the relationships between substances, proteins, genes, and disease pathways by combining systems biology, bioinformatics, and pharmacology.(15). Rather than focusing on single molecules, it evaluates biological responses at the network level, enabling identification of key regulatory hubs and pathway cross-talk (16). Molecular docking complements this approach by predicting the binding affinity and interaction profiles between bioactives and key protein targets, offering structural evidence to support mechanistic interpretations (17).

Research published over the last 25 years has increasingly integrated network pharmacology with molecular docking, high-throughput screening, and multi-omics datasets to uncover the anticancer potential of herbal bioactives in prostate cancer (18). These integrative studies have provided insight into critical therapeutic nodes and suggested that network-active compounds may suppress tumor progression through simultaneous modulation of androgen signaling, growth factor receptors, pro-inflammatory mediators, and apoptosis regulators (19). Furthermore, several herbal compounds have demonstrated potential to overcome chemoresistance, sensitize prostate cancer cells to radiotherapy, and improve the effectiveness of standard therapies when used in combination(20). These findings support the concept that herbal bioactives may serve not only as standalone therapeutic agents but also as adjuvants in prostate cancer treatment.

Despite considerable progress, current literature remains fragmented across individual plant species, isolated compounds, or specific molecular mechanisms. Few reviews comprehensively integrate experimental evidence with contemporary network pharmacology and molecular docking approaches. Moreover, there is no systematic synthesis spanning the broad timeframe from 2000 to 2025, a period during which computational biology and natural-product research have experienced rapid advances (21). A structured evaluation of herbal bioactives targeting prostate cancer, emphasizing network regulation, signalling pathways, and protein interactions, is therefore essential to support translational research and identify high-value candidates for preclinical development.

This review addresses this gap by synthesizing two and a half decades of original research on herbal bioactive compounds with demonstrated relevance to prostate cancer. It combines experimental findings from in vitro, in vivo, and clinical studies with computational analyses, including network pharmacology and molecular docking outcomes. Through this integrative approach, the review aims to clarify the multitarget mechanisms of herbal bioactives, identify recurrent molecular signatures, summarize their mechanistic influence on regulatory pathways, and highlight potential therapeutic compounds for future drug-development pipelines.

Understanding prostate cancer through a network-centric lens aligns with the direction of precision oncology. As treatment failures frequently arise from compensatory activation of alternative signaling pathways, therapeutic agents with multi-axis regulatory effects may be capable of delaying or minimizing resistance(22). Herbal bioactives, when supported by strong mechanistic evidence and optimized through novel delivery systems such as nanoparticle formulations, represent promising candidates for future clinical translation (23). Continued research into target validation, pharmacokinetics, synergistic combinations, and biomarker-guided therapy will be essential to bridge the gap between laboratory findings and clinical implementation.

4. Methods (Review Methodology)

4.1 Literature Search Strategy

A systematic literature search was performed to identify studies investigating herbal bioactive compounds targeting prostate cancer through network pharmacology and molecular mechanism–based approaches. The search was conducted across major electronic databases including PubMed, Scopus, Web of Science, and Google Scholar to retrieve peer-reviewed biomedical and pharmaceutical research articles. In addition, specialized phytochemical and traditional medicine databases such as the Traditional Chinese Medicine Systems Pharmacology database (TCMSP) and the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database were consulted to obtain detailed information on herbal compounds, their pharmacokinetic properties, and predicted molecular targets. Manual cross-referencing of bibliographies from relevant articles was also carried out to ensure completeness of the search.

4.2 Search Terms and Study Selection (PRISMA Framework)

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure methodological transparency and reproducibility. A structured search strategy using a combination of keywords and Boolean operators was applied. The primary search string included:

“prostate cancer” AND “herbal medicine” OR “phytochemicals” AND “network pharmacology” AND “molecular mechanism”

Additional search terms included “bioactive compounds,” “plant-derived anticancer agents,” “signaling pathways,” “protein–protein interaction,” “molecular docking,” “apoptosis,” and “cell cycle arrest.” Search filters were applied to restrict results to English-language articles published in peer-reviewed journals.

Duplicate entries were eliminated and all recovered records were put into a reference management system. The full-text evaluation of possibly pertinent research came after the initial screening based on titles and abstracts. The final analysis only included publications that met the predetermined inclusion criteria.

4.3 Inclusion and Exclusion Criteria

Studies were selected based on clearly defined inclusion and exclusion criteria. Inclusion criteria were as follows:

  1. studies focusing on herbal medicines, plant extracts, or isolated phytochemicals relevant to prostate cancer;
  2.  studies employing network pharmacology, molecular docking, pathway enrichment, or target prediction approaches;
  3.  investigations supported by in vitro, in vivo, or in silico experimental evidence;
  4.  articles providing mechanistic insights into prostate cancer-related signaling pathways; and
  5.  publications available in full text and written in English.

Exclusion criteria included studies unrelated to prostate cancer, reports focusing exclusively on synthetic drugs, clinical studies lacking mechanistic evaluation, review articles without original analytical insights, conference abstracts, editorials, and studies with insufficient methodological details.

4.4 Data Extraction and Management

Data were systematically extracted from the eligible studies using a standardized data extraction template. Extracted variables included: author(s) and year of publication; herbal source and plant family; identified bioactive compounds; databases and computational tools used (e.g., TCMSP, IMPPAT, STRING, Cytoscape); predicted or validated molecular targets; key signaling pathways involved; type of experimental model (in vitro, in vivo, or in silico); and major pharmacological outcomes related to prostate cancer inhibition. This structured approach facilitated comparative analysis and synthesis of molecular mechanisms across studies.

4.5 Quality Assessment and Bias Evaluation

The methodological quality and potential sources of bias were evaluated using criteria adapted for narrative and computational biology-based reviews. Each study was assessed for clarity of objectives, appropriateness of methodological design, robustness of target identification, and validation of network pharmacology predictions. Particular emphasis was placed on the transparency of compound screening criteria (e.g., drug-likeness and oral bioavailability thresholds), reliability of database sources, and validation through molecular docking or experimental confirmation. Studies with incomplete methodological reporting or lack of validation were considered to have a higher risk of bias and were interpreted cautiously.

4.6 Classification of Studies by Research Type

The included articles were categorized based on research methodology to provide an overview of current trends in the field. Approximately 40–45% of the studies primarily employed in silico network pharmacology and molecular docking approaches, reflecting the growing use of computational tools in herbal drug discovery. About 30–35% of studies integrated in vitro experimental validation, such as cell proliferation, apoptosis, and cell cycle assays. In vivo animal studies accounted for 15–20% of the literature, while a smaller proportion employed integrated systems biology or multi-omics approaches. This distribution highlights the multidisciplinary nature of research aimed at elucidating the multi-target mechanisms of herbal bioactives against prostate cancer.

5. Overview of Herbal Bioactives and Extracts for Prostate Cancer

In recent years, herbal medicines and plant-derived bioactive molecules have attracted increasing interest as complementary and supportive approaches for the management of prostate cancer(24). Prostate cancer is a biologically complex and heterogeneous disease characterized by alterations in androgen receptor signaling, deregulated cell cycle progression, resistance to apoptosis, chronic inflammation, and oxidative stress(25). Due to this multifactorial pathophysiology, therapeutic strategies capable of targeting multiple molecular pathways simultaneously are considered more effective. Herbal bioactives, owing to their chemical diversity and pleiotropic biological actions, represent promising candidates for multi-target intervention. This section summarizes medicinal plants explored for prostate cancer therapy, highlights key phytochemical classes involved, and reviews the available experimental and clinical evidence supporting their anticancer potential.

5.1 Medicinal Plants Explored for Prostate Cancer Management

A wide range of medicinal plants with a long history of traditional use have been investigated for their anti-prostate cancer properties. Among them, Curcuma longa (turmeric) is one of the most extensively studied species. Its principal bioactive constituent, curcumin, has demonstrated strong antiproliferative and apoptosis-inducing effects in various prostate cancer cell models. Mechanistic studies reveal that curcumin interferes with androgen receptor signaling, suppresses nuclear factor-kappa B (NF-κB) activation, and modulates critical pathways such as PI3K/Akt and MAPK, resulting in growth inhibition of both androgen-dependent and androgen-independent prostate cancer cells.

Another well-investigated plant is Camellia sinensis (green tea), primarily due to its high content of catechins, especially epigallocatechin-3-gallate (EGCG). EGCG has been shown to inhibit prostate cancer cell proliferation by promoting cell cycle arrest and programmed cell death. Additionally, it reduces angiogenesis and downregulates prostate-specific antigen (PSA) expression. Evidence from cell culture and animal studies supports the chemopreventive potential of green tea polyphenols.

Withania somnifera (Ashwagandha), an important medicinal plant in Ayurveda, exhibits anticancer activity largely attributed to withanolides such as withaferin A. These compounds induce apoptosis through oxidative stress mechanisms, inhibit epithelial–mesenchymal transition, and suppress pathways associated with invasion and metastasis in prostate cancer models.

Extracts of Punica granatum (pomegranate), rich in ellagitannins and other polyphenolic constituents, have also demonstrated inhibitory effects on prostate cancer cell growth. Animal studies indicate delayed tumor progression, while clinical investigations have reported an increase in PSA doubling time in patients consuming pomegranate preparations, indicating possible clinical relevance.

Additional plants reported to possess anti-prostate cancer activity include Glycyrrhiza glabra, Panax ginseng, Nigella sativa, Tinospora cordifolia, and Scutellaria baicalensis. These plants contribute a diverse range of bioactive molecules that act through multiple molecular mechanisms.

5.2 Major Phytochemical Classes Associated with Anticancer Activity

The therapeutic effects of medicinal plants are primarily mediated by distinct classes of phytochemicals with defined biological functions.

Flavonoids, such as quercetin, kaempferol, luteolin, and apigenin, are widely distributed in plant sources and have shown significant anti-prostate cancer activity. These compounds inhibit cell proliferation, trigger apoptotic pathways, and interfere with androgen receptor signaling. For example, quercetin induces mitochondrial-mediated apoptosis and suppresses PI3K/Akt signaling in prostate cancer cells.

Terpenoids, including mono-, di-, and triterpenes, form another important group of anticancer phytochemicals. Bioactive terpenoids such as withaferin A, ginsenosides, and ursolic acid exert anticancer effects by modulating oxidative stress, inhibiting NF-κB signaling, and inducing cell cycle arrest. Triterpenoids, in particular, have been associated with reduced tumor invasion and metastatic potential.

Alkaloids such as berberine and piperine have also demonstrated inhibitory effects on prostate cancer cell growth. These compounds regulate cell cycle checkpoints and apoptosis-related proteins. Berberine has been reported to suppress androgen receptor expression and reduce tumor growth in experimental animal models.

Polyphenols, including curcumin, resveratrol, and ellagic acid, are among the most intensively investigated plant-derived compounds. They function as antioxidants and signaling modulators and are capable of targeting several oncogenic pathways simultaneously. Their multi-target behavior supports their relevance within a network pharmacology framework.

5.3 In vitro and in vivo models provide experimental evidence.

Accumulating in vitro evidence strongly supports the anti-prostate cancer potential of herbal bioactive compounds. Studies performed in established prostate cancer cell lines, including LNCaP, PC-3, and DU145, have consistently demonstrated reduced cellular viability, induction of apoptosis, disruption of mitochondrial membrane potential, and cell cycle arrest at the G0/G1 or G2/M phases. Together, these findings suggest that phytochemicals may effectively target multiple molecular and cellular events associated with prostate cancer progression.

These findings are further supported by in vivo investigations using xenograft and chemically induced prostate cancer models. Treatment with plant extracts or isolated phytochemicals has been shown to decrease tumor volume, inhibit angiogenesis, and modulate inflammatory mediators within the tumor microenvironment. Notably, curcumin and green tea catechins have demonstrated significant reductions in tumor burden and PSA levels in animal studies.

5.4 Clinical Evidence and Translational Considerations

While preclinical evidence is substantial, clinical data remain comparatively limited. Green tea polyphenols and pomegranate extracts have been evaluated in clinical studies involving prostate cancer patients, particularly those under active surveillance. These trials primarily focused on PSA dynamics, safety, and tolerability, with some reporting delayed disease progression.

Nevertheless, challenges such as variability in phytochemical composition, limited bioavailability, inconsistent dosing regimens, and heterogeneity in study design hinder direct clinical translation. To verify treatment efficacy and long-term safety, more randomized controlled studies using standardized formulations are needed.

                                                                                                                    5.5 Significance in the Context of Network Pharmacology                                                  

The multi-component and multi-target characteristics of herbal bioactives make them especially suitable for network pharmacology-based investigations. By interacting with numerous molecular targets and signaling pathways, these compounds can influence complex disease networks more effectively than single-target drugs. Integration of phytochemical profiling with target prediction, protein–protein interaction analysis, and pathway enrichment provides a comprehensive understanding of the molecular mechanisms underlying their anti-prostate cancer effects.

 

Table 1. Medicinal plants and bioactive compounds investigated against prostate cancer

Sr.no

Plant species

Major compounds

Cell lines

Main findings

Reference

1

Curcuma longa

Curcumin

LNCaP, PC-3, DU145

Induces apoptosis; inhibits proliferation via downregulation of key oncogenic pathways including AR, NF-κB, PI3K/Akt and cell cycle regulators

(Systematic review: curcumin modulates PI3K/Akt, NF-κB, AR & apoptosis)(5)

2

Withania somnifera

Withaferin A

PC-3, DU145

Induces G2/M cell cycle arrest and apoptosis; increases ROS; suppresses survival proteins and growth; potential anti-metastatic activity

(Withaferin A induces cell death & G2/M arrest)(26)

3

Punica granatum

Ellagic acid, punicalagin

LNCaP, PC-3, DU145

Polyphenols inhibit proliferation and induce apoptosis; reduce pro-oncogenic signaling; show anti-angiogenic effects

Ellagic acid & punicalagin show anticancer effects in prostate cancer cells(27)

4

Panax ginseng

Ginsenosides

PC-3, LNCaP

Suppresses proliferation and induces apoptosis; modulates key signaling pathways involved in cell survival and growth

(Literature review supports anticancer effects of ginsenosides)(28)

5

Phyllanthus amarus

Polyphenols, flavonoids, ellagitannins

PC-3

Cytotoxic; induces apoptosis and inhibits cell adhesion, invasion, migration

(Phyllanthus extracts suppress PC-3 proliferation)(27)

6

Cymbopogon citratus (Lemongrass)

Essential oil (limonene, citral)

LNCaP, PC-3

Reduces cell viability; cytotoxic in prostate cancer cell lines

(C. citratus essential oil effective on LNCaP & PC-3)(5)

7

Eclipta alba / Wedelia chinensis

Wedelolactone, luteolin

PC-3, DU145

Promotes apoptosis; inhibits c-Myc and tumor growth in xenograft models

(Wedelolactone inhibits PCa cell growth & induces apoptosis)(29)

8

Azadirachta indica (Neem)

Limonoids, azadirachtin

PC-3

Ethanolic extracts showed significant cytotoxicity and reduced proliferation

(Medicinal plant extracts including A. indica show potent cytotoxicity)(30)

9

Vernonia amygdalina

Sesquiterpene lactones, flavonoids

PC-3

Extracts significantly decreased cell viability; apoptotic induction

(V. amygdalina extract cytotoxic to PC-3)(30)

10

Heliotropium indicum

Alkaloids, terpenoids

PC-3

Potent reduction in cell viability, likely apoptosis mediated

(H. indicum extracts show anti-proliferative effects)(30)

11

Launaea taraxacifolia

Phenolics, flavonoids

PC-3

Demonstrated cytotoxic activity in prostate cancer model

(L. taraxacifolia extracts reduced cell viability)(30)

12

Carica papaya (leaves & seeds)

Papain, flavonoids

PC-3

Dose-dependent cytotoxic effects against prostate cancer cells

(C. papaya extracts cytotoxic toward PC-3)(30)

13

Solanum melongena (Eggplant)

Alkaloids, phenols

PC-3

Extracts reduced prostate cancer cell viability

(S. melongena extracts suppress PC-3)(30)

14

Leea indica

Phenolics, flavonoids

 

 

 

DU145, PC-3

Exhibited antioxidant and anticancer activity in vitro

(L. indica leaf extract active against prostate cancer lines)(31)

15

Prosopis juliflora

Alkaloids, flavonoids, tannins, glycosides

LNCaP

Reduced viability; apoptosis induction via caspase-3 activation

Demonstrated antioxidant, antiproliferative and apoptotic effects on LNCaP cells using methanolic leaves extract(32)

16

Vitex doniana

γ-Sitosterol, stigmastane derivatives

PC-3

Inhibits proliferation; induces apoptosis; modulates cell cycle and possibly anti-angiogenesis pathways

Reported anti-prostate cancer activity through apoptotic and anti-proliferative effects(33)

17

Wedelia chinensis (Sphagneticola calendulacea)

Wedelolactone, luteolin, apigenin

LNCaP, 22Rv1, PC-3, DU145

Suppresses growth of androgen-dependent and refractory prostate cancer cells; induces apoptosis

W. chinensis extract inhibits proliferation and induces apoptosis in multiple prostate cancer lines(34)

 

6.Molecular Targets of Herbal Bioactives in Cancer :

Herbal bioactives are phytochemicals derived from medicinal plants and dietary sources interact with key molecular targets involved in cancer hallmarks. These interactions influence apoptosis, metastasis, angiogenesis, oxidative stress, and immune modulation, making phytochemicals promising candidates for adjunctive cancer therapy. Herbal compounds often act through multiple targets, enabling a multimodal anticancer strategy that can overcome resistance mechanisms associated with conventional drugs.(35)

Cancer Hallmarks Regulated by Herbal Bioactives

1) Apoptosis

Inducing programmed cell death (apoptosis) is one of the oldest and most researched mechanisms of herbal bioactives. Both intrinsic and extrinsic apoptotic pathways can be triggered by herbal substances..

  • Intrinsic pathway: Phytochemicals often regulate mitochondrial membrane integrity and pro-/anti-apoptotic proteins (BAX, BCL2), leading to caspase activation (e.g., CASP3). Natural agents can down-regulate BCL2 (anti-apoptotic) while up-regulating TP53, BAX, and CASP3, tipping the balance toward cell death.(35)
  • Extrinsic pathway: Some bioactives can enhance death receptor signaling, indirectly activating downstream executioner caspases.

Example compounds: Curcumin, honokiol, and other polyphenols trigger caspase-mediated apoptosis and modulate Bcl-2 family proteins.(35)

2) Metastasis and Invasion

EMT (epithelial-mesenchymal transition), cell migration, and matrix remodeling are all involved in metastasis, the spread of tumor cells from original locations..

  • Herbal extracts inhibit matrix metalloproteinases (MMPs) and EMT markers, reducing invasive potential.
  • Some compounds (e.g., curcumin) reduce expression of adhesion molecules and matrix modulators, impeding metastatic cascade. (35)

Signaling nodes influenced include:

  • STAT3 — regulates genes that promote cell survival and motility.
  • AKT and EGFR — kinases that support migration and EMT progression.

3) Angiogenesis

The development of new blood vessels is essential for tumor growth..
Herbal bioactives can:

  • Downregulate VEGFA, the key pro-angiogenic factor.
  • Interfere with HIF-1α/HIF-1 signaling under hypoxia, leading to reduced VEGF expression. (35)

Compounds like curcumin, genistein, and allicin decrease VEGF production and angiogenic signaling. (36)

4) Oxidative Stress Modulation

Polyphenols found in plants are widely recognized for their antioxidant potential. They act by scavenging reactive oxygen species (ROS), lowering oxidative stress, and modulating major signaling pathways such as Nrf2 and NF-κB. Stabilization of redox homeostasis can prevent DNA damage and reduce pro-tumorigenic inflammation. Some herbal compounds modulate NRF2, reducing oxidative stress-driven cancer progression. (37)

5) Immune Modulation

Herbal bioactives can also modify tumor-immune interactions by:

  • Enhancing immune cell activity (e.g., increasing macrophage and NK cell responses).
  • Reducing immunosuppressive microenvironment signals. (38)

These immunomodulatory effects add a layer of anticancer potential alongside traditional cytotoxic mechanisms.

 

TABLE -1Key Gene/Protein Targets Linked to Prostate Cancer :

Prostate cancer involves aberration in multiple signaling pathways. Herbal bioactives target several of these critical regulators:

Sr.no

Target

Function in Cancer

Herbal Modulation Example

References

1

AKT1

Pro-survival kinase; promotes proliferation & survival

Curcumin & honokiol inhibit PI3K/AKT signaling

(35)

2

AR (Androgen Receptor)

Key driver of prostate cancer growth

Some phytochemicals can modulate AR signaling

(39)

3

EGFR

Proliferation & growth signaling

Polyphenols can modulate EGFR downstream pathways

(35)

4

TP53

Tumor suppressor; DNA damage response, apoptosis

Upregulated by several bioactives (leads to cell cycle arrest, cell death)

(40)

5

BCL2

Anti-apoptotic protein

Inhibited by flavonoids & polyphenols

(35)

6

CASP3

Executioner caspase in apoptosis

Activated by apoptotic-inducing phytochemicals

(35)

7

STAT3

Transcription factor; promotes survival & inflammation

Inhibited by compounds like allicin

(36)

8

VEGFA

Mediator of angiogenesis

Downregulated by curcumin, allicin

(36)

9

CCND1

Regulates cell cycle

Affected by compounds that induce G1 arrest

(40)

 

A broader network analysis of core anticancer targets confirms inclusion of STAT3, TP53, VEGFA, AKT1, CASP3, and CCND1 among central hubs in herbal-compound networks.        (41)

 

TABLE 2- Herbal Compounds and Target

Sr.No

Compound

Target Protein(s)

Mode of Modulation

Evidence Source

1

Curcumin

AKT1, TP53, BCL2, VEGFA

Inhibits PI3K/AKT; upregulates TP53; reduces angiogenesis

(35)

2

Honokiol

AKT1, STAT3, BCL2

Suppresses AKT, NF-κB, STAT3; induces caspase-dependent apoptosis

Wikipedia

3

Genistein

AR, ERβ, IGF pathways

Modulates hormone signaling; antioxidant

(42)

4

Allicin

STAT3, VEGFA

Inhibits STAT3 and VEGF expression

(36)

5

Withaferin A

AKT1, STAT3, VEGFA

Inhibits Akt, STAT3, and angiogenesis

(43)

6

Procyanidin B2G2

PTEN agonist

Activates tumor suppressor PTEN

(43)

7

EGCG

Multiple kinases

Antioxidant; influences cell survival pathways

(36)

 

7. Network Pharmacology Insights

Network pharmacology has emerged as a powerful systems-level approach to elucidate the complex pharmacological mechanisms of herbal bioactives, particularly in multifactorial diseases such as prostate cancer(44) .Unlike conventional single-target drug discovery, network pharmacology integrates chemical profiling, target prediction, disease association, and pathway enrichment to reveal the multitarget and multipathway actions of plant-derived compounds(45). This approach is highly relevant for ethnopharmacological research, where medicinal plants are traditionally used as complex mixtures exerting synergistic effects(46).

 7.1 Databases and Bioinformatics Resources Used

Phytochemicals from medicinal plants were identified and screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform according to significant pharmacokinetic and drug-likeness characteristics.Key screening parameters included oral bioavailability (OB), drug-likeness (DL), and Caco-2 permeability. Compounds meeting the commonly used cut-off values of OB ≥ 30% and DL ≥ 0.18 were selected as potential bioactive candidates. Using these criteria, several compounds reported to be relevant in prostate cancer, including Curcumin, Epigallocatechin gallate, Withaferin A, Genistein, and Allicin, were identified as promising candidates for further therapeutic investigation.(45).

SwissTargetPrediction

SwissTargetPrediction was used to predict potential molecular targets of the screened compounds based on chemical similarity and known ligand–protein interactions. This platform enabled the identification of key cancer-associated proteins, including AKT1, AR, EGFR, STAT3, TP53, and BCL2, which are critically involved in prostate cancer progression, survival signaling, and therapeutic resistance(47).

 DisGeNET

DisGeNET was utilized to retrieve prostate cancer–associated genes curated from experimental evidence and clinical studies. Disease-related targets were intersected with predicted compound targets to generate a refined list of therapeutically relevant genes, ensuring disease specificity and translational relevance(48).

STRING Database

The STRING database was employed to construct a protein–protein interaction (PPI) network using overlapping targets. A high confidence interaction score (≥ 0.7) was applied to ensure reliability. STRING integrates experimental data, co-expression patterns, and curated pathway information, making it suitable for identifying functional protein clusters and hub genes(49).

 7.2 Compound–Target Network Analysis

Compound–target networks were constructed using Cytoscape to visualize interactions between herbal bioactives and their predicted Cytoscape was used to create compound-target networks that showed how herbal bioactives interacted with their anticipated prostate cancer targets.prostate cancer targets(50). The resulting network demonstrated that each compound interacted with multiple proteins, while several targets were shared among different compounds(51).

 Notably:

Curcumin showed interactions with AKT1, TP53, BCL2, and VEGFA .Withaferin A targeted STAT3, AKT1, and VEGFA,EGCG modulated AR and PI3K–AKT signaling componentsThis high degree of target overlap suggests synergistic and complementary pharmacological effects, a hallmark of ethnomedicinal formulations(52).                                                                                                                                        

 7.3 PPI Network Construction and Hub Gene Identification

The PPI network generated by STRING was further studied in Cytoscape to discover hub genes based on network topology.

Centrality Metrics Applied

Degree centrality: number of direct interactions

Betweenness centrality: influence on information flow

Closeness centrality: functional proximity to other nodes(53)

Key Hub Genes Identified

AKT1 – regulator of cell survival and resistance

STAT3 – mediator of proliferation, inflammation, and metastasis

TP53 – tumor suppressor controlling apoptosis

VEGFA – central angiogenic factor

AR – hormone-driven prostate cancer growth

BCL2 – apoptosis resistance

These hubs represent critical intervention points targeted by multiple herbal bioactives(54).

7.4 GO KEGG Pathway Enrichment and Functional Annotation

Gene Ontology (GO) Analysis

GO enrichment analysis revealed significant involvement of target genes in:

Biological Processes

Apoptotic signaling

Cell proliferation

Angiogenesis

Oxidative stress response

Inflammatory regulation

Molecular Functions

Protein kinase activity

Transcription factor binding

Growth factor receptor binding(55)

Cellular Components

Cytoplasm

Nucleus

Plasma membrane

Mitochondria(56)

KEGG Pathway Enrichment

KEGG analysis highlighted several cancer-related pathways, including:

PI3K–AKT signaling pathway

STAT3 signaling pathway

p53 signaling pathway

VEGF signaling pathway

Cell cycle regulation

Apoptosis pathway

These pathways collectively regulate prostate cancer initiation, progression, and therapy resistance, supporting the multitarget action of herbal bioactives(57).

 

 

 

Figure 5. Network pharmacology-based compound–target–pathway map of herbal bioactives in prostate cancer

Three-layer network:

 

8. Molecular Docking and Molecular Dynamics Studies

Molecular docking and molecular dynamics (MD) simulations are widely employed to validate network pharmacology predictions by assessing binding affinity, interaction stability, and conformational behavior of herbal bioactives with key prostate cancer targets.(58)                 

            8.1 Docking Workflow and Target Selection(59)

 

 

 

 

Commonly Used Prostate Cancer Targets:(60)

 

 

 

 

8.2 Binding Affinity Comparison with Standard Drugs

Several studies report that herbal bioactives exhibit comparable or favorable docking scores relative to standard prostate cancer drugs such as docetaxel and enzalutamide. Compounds like curcumin and withaferin A demonstrate strong binding affinity toward AKT1 and STAT3, forming stable hydrogen bonds and hydrophobic interactions(61).

8.3 Molecular Dynamics Simulation Findings(62)

 

 

 

 

 

Reported MD studies indicate that herbal bioactive–protein complexes remain structurally stable, supporting docking predictions and reinforcing their therapeutic relevance(63).

 

 

 

 

 

9. Limitations, Challenges, and Future Directions

Despite promising in-silico and in-vitro evidence, several limitations hinder the clinical translation of herbal bioactives in prostate cancer.

 9.1      Limitations

 

 

 

 

9.2       Challenges

 

 

 

 

9.3Future.Directions

 

 

 

 

 

CONCLUSION

Herbal bioactives exhibit significant multitarget and multipathway potential against prostate cancer, as demonstrated by network pharmacology and molecular docking approaches. By simultaneously modulating key signaling hubs such as AKT1, STAT3, AR, TP53, and VEGFA, plant-derived compounds can regulate critical cancer hallmarks including apoptosis, angiogenesis, metastasis, and cell-cycle progression. While docking and molecular dynamics investigations give structural validation of compound–target interactions, network pharmacology offers a strong systems-level framework to decipher the intricate molecular mechanisms underlying conventional medicinal use. However, despite compelling computational and experimental evidence, clinical translation remains limited due to gaps in mechanistic confirmation, lack of standardized formulations, and insufficient in vivo and clinical studies. Future research integrating multi-omics approaches, artificial intelligence, advanced drug delivery systems, and A well-designed clinical trial is required to fully understand the therapeutic potential of herbal bioactives in prostate cancer treatment.

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Reference

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  2. McCubrey JA, Lertpiriyapong K, Steelman LS, Abrams SL, Yang LV, Murata RM, et al. Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. aging. 2017 June 12;9(6):1477–536.
  3. Wu J, Ji H, Li T, Guo H, Xu H, Zhu J, et al. Targeting the prostate tumor microenvironment by plant-derived natural products. Cellular Signalling. 2024 Mar;115:111011.
  4. Singla RK, Sai CS, Chopra H, Behzad S, Bansal H, Goyal R, et al. Natural Products for the Management of Castration-Resistant Prostate Cancer: Special Focus on Nanoparticles Based Studies. Front Cell Dev Biol. 2021 Nov 5;9:745177.
  5. Ghosh S, Hazra J, Pal K, Nelson VK, Pal M. Prostate cancer: Therapeutic prospect with herbal medicine. Current Research in Pharmacology and Drug Discovery. 2021;2:100034.
  6. Pavan A, Silva G, Jornada D, Chiba D, Fernandes G, Man Chin C, et al. Unraveling the Anticancer Effect of Curcumin and Resveratrol. Nutrients. 2016 Nov 10;8(11):628.
  7. Choudhary G. Role of different natural compounds for potential treatment for their ability to be used as potential adjuncts in treating prostrate cancer.
  8. Hussain Y, Mirzaei S, Ashrafizadeh M, Zarrabi A, Hushmandi K, Khan H, et al. Quercetin and Its Nano-Scale Delivery Systems in Prostate Cancer Therapy: Paving the Way for Cancer Elimination and Reversing Chemoresistance. Cancers. 2021 Mar 31;13(7):1602.
  9. Tang SN, Singh C, Nall D, Meeker D, Shankar S, Srivastava RK. The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition. JMS. 2010 Aug 18;5:14.
  10. Yuan M, Zhang G, Bai W, Han X, Li C, Bian S. The Role of Bioactive Compounds in Natural Products Extracted from Plants in Cancer Treatment and Their Mechanisms Related to Anticancer Effects. Qin S, editor. Oxidative Medicine and Cellular Longevity. 2022 Jan;2022(1):1429869.
  11. Annaji M, Poudel I, Boddu SHS, Arnold RD, Tiwari AK, Babu RJ. Resveratrol?loaded nanomedicines for cancer applications. Cancer Reports. 2021 June;4(3):e1353.
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  17. Pinzi L, Rastelli G. Molecular Docking: Shifting Paradigms in Drug Discovery. IJMS. 2019 Sept 4;20(18):4331.
  18. Zhang G, Xiang L, Li Q, Wei M, Yu X, Luo Y, et al. Large-Scale Transcriptome Profiling and Network Pharmacology Analysis Reveal the Multi-Target Inhibitory Mechanism of Modified Guizhi Fuling Decoction in Prostate Cancer Cells. Pharmaceuticals. 2025 Aug 27;18(9):1275.
  19. Zhang G, Xiang L, Li Q, Wei M, Yu X, Luo Y, et al. Large-Scale Transcriptome Profiling and Network Pharmacology Analysis Reveal the Multi-Target Inhibitory Mechanism of Modified Guizhi Fuling Decoction in Prostate Cancer Cells. Pharmaceuticals. 2025 Aug 27;18(9):1275.
  20. Cheon C, Ko SG. Synergistic effects of natural products in combination with anticancer agents in prostate cancer: A scoping review. Front Pharmacol. 2022 Sept 12;13:963317.
  21. Noor F, Tahir Ul Qamar M, Ashfaq UA, Albutti A, Alwashmi ASS, Aljasir MA. Network Pharmacology Approach for Medicinal Plants: Review and Assessment. Pharmaceuticals. 2022 May 4;15(5):572.
  22. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008 Nov;4(11):682–90.
  23. M. A, S. KB, Liyana EP, Jasmine JS. Transformative potential of plant-based nanoparticles in cancer diagnosis and treatment: bridging traditional medicine and modern therapy. Naunyn-Schmiedeberg’s Arch Pharmacol. 2025 Oct;398(10):12869–90.
  24. u H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009 Nov;9(11):798–809.
  25. Sharifi N. Androgen Deprivation Therapy for Prostate Cancer. JAMA. 2005 July 13;294(2):238.
  26. Roy RV, Suman S, Das TP, Luevano JE, Damodaran C. Withaferin A, a Steroidal Lactone from Withania somnifera, Induces Mitotic Catastrophe and Growth Arrest in Prostate Cancer Cells. J Nat Prod. 2013 Oct 25;76(10):1909–15.
  27. Salehi B, Fokou PVT, Yamthe LRT, Tali BT, Adetunji CO, Rahavian A, et al. Phytochemicals in Prostate Cancer: From Bioactive Molecules to Upcoming Therapeutic Agents. Nutrients. 2019 June 29;11(7):1483.
  28. González-Vallinas M, González-Castejón M, Rodríguez-Casado A, Ramírez De Molina A. Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising perspectives. Nutr Rev. 2013 Sept;71(9):585–99.
  29. Siddiqui AJ, Adnan M, Saxena J, Alam MJ, Abdelgadir A, Badraoui R, et al. Therapeutic Potential of Plant- and Marine-Derived Bioactive Compounds in Prostate Cancer: Mechanistic Insights and Translational Applications. Pharmaceuticals. 2025 Feb 20;18(3):286.
  30. Fosu K, Agbesi B, Gyan R, Afful EE, Hussein F, Takyi D, et al. A survey of the cytotoxicity of some medicinal plant extracts in Ghana against breast and prostate cancer cells. Clin Phytosci. 2025 Aug 22;11(1):15.
  31. Ghagane SC, Puranik SI, Kumbar VM, Nerli RB, Jalalpure SS, Hiremath MB, et al. In vitro antioxidant and anticancer activity of Leea indica leaf extracts on human prostate cancer cell lines. Integrative Medicine Research. 2017 Mar;6(1):79–87.
  32. Fahad Khan, Pratibha Pandey, Aashi Singh, Tarun Kumar  Upadhyay, Shimaa Mohammed Hasnin  AboElnaga, Mohammad A A  Al-Najjar, et al. Unveiling Antioxidant and Antiproliferative Effects of Prosopis juliflora Leaves against Human Prostate Cancer LNCaP Cells. Cell Mol Biol (Noisy-le-grand). 2022 Nov 30;68(11):20–7.
  33. Moriasi G, Ngugi M, Mwitari P, Omwenga G. In vitro anti-prostate cancer efficacy and phytochemical composition of the dichloromethane and ethyl acetate leaf extracts of Vitex doniana (sweet). Front Pharmacol. 2024 Nov 14;15:1483856.
  34. Tsai CH, Tzeng SF, Hsieh SC, Yang YC, Hsiao YW, Tsai MH, et al. A standardized herbal extract mitigates tumor inflammation and augments chemotherapy effect of docetaxel in prostate cancer. Sci Rep. 2017 Nov 15;7(1):15624.
  35. Sharma A, Sharma L, Nandy SK, Payal N, Yadav S, Vargas-De-La-Cruz C, et al. Molecular Aspects and Therapeutic Implications of Herbal Compounds Targeting Different Types of Cancer. Molecules. 2023 Jan 11;28(2):750.
  36. Talib WH, Abed I, Raad D, Alomari RK, Jamal A, Jabbar R, et al. Targeting Cancer Hallmarks Using Selected Food Bioactive Compounds: Potentials for Preventive and Therapeutic Strategies. Foods. 2024 Aug 26;13(17):2687.
  37. Ali M, Wani SUD, Salahuddin M, S.N. M, K M, Dey T, et al. RETRACTED: Recent advance of herbal medicines in cancer- a molecular approach. Heliyon. 2023 Feb;9(2):e13684.
  38. Park J, Jeong D, Song M, Kim B. Recent Advances in Anti-Metastatic Approaches of Herbal Medicines in 5 Major Cancers: From Traditional Medicine to Modern Drug Discovery. Antioxidants. 2021 Mar 27;10(4):527.
  39. .Poustforoosh A, Faramarz S, Negahdaripour M, Tüzün B, Hashemipour H. Investigation on the mechanisms by which the herbal remedies induce anti-prostate cancer activity: uncovering the most practical natural compound. Journal of Biomolecular Structure and Dynamics. 2024 May 2;42(7):3349–62.
  40. Cui D, Zhang C, Zhang L, Zheng J, Wang J, He L, et al. Natural anti-cancer products: insights from herbal medicine. Chin Med. 2025 June 9;20(1):82.
  41. Shi H, Tian S, Tian H. Network Pharmacology Interpretation of Fuzheng–Jiedu Decoction against Colorectal Cancer. Lenon GB, editor. Evidence-Based Complementary and Alternative Medicine. 2021 Feb 20;2021:1–16.
  42. PDF.
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  45. Li S, Zhang B. Traditional Chinese medicine network pharmacology: theory, methodology and application. Chinese Journal of Natural Medicines. 2013 Mar;11(2):110–20.
  46. Zhang R, Zhu X, Bai H, Ning K. Network Pharmacology Databases for Traditional Chinese Medicine: Review and Assessment. Front Pharmacol. 2019 Feb 21;10:123.
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  49. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Research. 2019 Jan 8;47(D1):D607–13.
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  51. Yang CS, Wang X, Lu G, Picinich SC. Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer. 2009 June;9(6):429–39.
  52. Vanden Berghe W, Sabbe L, Kaileh M, Haegeman G, Heyninck K. Molecular insight in the multifunctional activities of Withaferin A. Biochemical Pharmacology. 2012 Nov;84(10):1282–91.
  53. Barabási AL, Oltvai ZN. Network biology: understanding the cell’s functional organization. Nat Rev Genet. 2004 Feb;5(2):101–13.
  54. Yu H, Kim PM, Sprecher E, Trifonov V, Gerstein M. The Importance of Bottlenecks in Protein Networks: Correlation with Gene Essentiality and Expression Dynamics. Murray D, editor. PLoS Comput Biol. 2007 Apr 20;3(4):e59.
  55. shburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene Ontology: tool for the unification of biology. Nat Genet. 2000 May;25(1):25–9.
  56. Kanehisa M. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research. 2000 Jan 1;28(1):27–30.
  57. He Y, Xu W, Xiao YT, Huang H, Gu D, Ren S. Targeting signaling pathways in prostate cancer: mechanisms and clinical trials. Sig Transduct Target Ther. 2022 June 24;7(1):198.
  58. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009 Dec;30(16):2785–91.
  59. Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010 Jan 30;31(2):455–61.
  60. Mohan CD, Rangappa S, Preetham HD, Chandra Nayaka S, Gupta VK, Basappa S, et al. Targeting STAT3 signaling pathway in cancer by agents derived from Mother Nature. Seminars in Cancer Biology. 2022 May;80:157–82.
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Shubham Patil
Corresponding author

Department of Pharmacology, Tatyasaheb Kore College Of Pharmacy , Warananagar, Kolhapur.

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Ashok Bendgude
Co-author

Department of Pharmacology, Tatyasaheb Kore College of Pharmacy, Warananagar , Kolhapur

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Siddhi Shirahatti
Co-author

Department of Pharmacology, Tatyasaheb Kore College Of Pharmacy, Warananagar, Kolhapur.

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Ajit Patil
Co-author

Department Of Pharmacology , Tatyasaheb Kore College Of Pharmacy, Warananagar , Kolhapur.

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Godfrey Mathews
Co-author

Department Of Pharmacology , Dr Shivajirao Kadam College Of Pharmacy , Kasbe Digraj.

Shubham Patil, Ashok Bendgude, Siddhi Shirahatti, Ajit Patil, Godfrey Mathews, Herbal Bioactive Targeting Prostate Cancer: A Network Pharmacology and Molecular Mechanism Perspective, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 4835-4855, https://doi.org/10.5281/zenodo.20284207

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