Computational Pharmacology Analysis of Lycopene to Identify Its Targets and Biological Effects in Humans

Abstract

Lycopene exhibits a broad spectrum of biological activities with potential therapeutic applications. Despite its established antioxidant and anti-inflammatory properties, the molecular basis for its pharmacological actions remains incompletely defined. Here we investigated the molecular targets, pharmacodynamic feasibility, and tissue-specific expression of lycopene targets using a computational pharmacology approach combined with affinity and protein–protein interaction (PPI) analyses. Lycopene-associated human protein targets were predicted using a Swiss target screening platform. Molecular docking was used to estimate binding affinities, and concentration-affinity (CA) ratios were calculated based on physiologically relevant plasma concentrations (75–210 nM). PPI networks of lycopene targets were constructed to identify highly connected targets, and tissue expression analysis was assessed for high-affinity targets using protein-level data from the Human Protein Atlas database. Of the 94 predicted targets, 37% were nuclear receptors and 18% were Family A G Protein Coupled Receptors (GPCRs). Among the top 15 high-affinity targets, nuclear receptors and GPCRs comprised 40% and 26.7%, respectively. Twenty targets had affinities < 10 μM, with six key targets (MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24) showing submicromolar binding. CA ratio analysis identified MAP2K2, SCN2A, and SLC6A5 as pharmacodynamically feasible targets (CA > 1). PPI analysis revealed 32 targets with high interaction and 9 with significant network connectivity. Seven targets (TRIM24, GRIN1, NTRK1, FGFR1, NTRK3, CHRNB4, and PIK3CD) showed both high affinity and centrality in the interaction network. The expression profiling of submicromolar targets revealed widespread tissue distribution for MAP2K2 and SCN3A, while SCN2A, TOP2A, and TRIM24 showed more restricted expression patterns. This integrative analysis identifies a subset of lycopene targets with both high affinity and pharmacological feasibility, particularly MAP2K2, SCN2A, and TRIM24. Lycopene appears to exert its biological effects through modulation of interconnected signalling networks involving nuclear receptors, GPCRs, and ion channels. These findings support the potential of lycopene as a multi-target therapeutic agent and provide a rationale for future experimental and clinical validation.

1. Introduction

Lycopene, a naturally occurring lipophilic dietary carotenoid found predominantly in tomatoes and other red-coloured fruits/vegetables has been extensively studied for its health benefits. Lycopene concentrations per 100 g for some common sources are as follows: guava: 5204 micrograms (µg), cooked tomatoes: 3041 µg, watermelon: 4532 µg, pink grapefruit: 1419 µg, papaya: 1828 µg, red bell peppers (cooked): 484 µg, persimmon: 159 µg, asparagus (cooked): 30 µg, and red cabbage: 20 µg. It is important to note that lycopene concentrations can vary based on factors such as ripeness, variety, and growing conditions [1,2,3]. The global lycopene market was valued at approximately Euro 160 million in 2023 and is projected to grow at a compound annual growth rate (CAGR) of 5.1% from 2024 to 2030 [4,5]. The average daily lycopene intake ranges from 5 to 11 mg per capita [4,5]. Epidemiological studies have associated the high dietary intake of lycopene with reduced risks of chronic diseases such as cardiovascular ailments and certain cancers. These observations have spurred extensive research into the bioactive properties of lycopene, particularly its antioxidant and anti-inflammatory effects [6,7].

Lycopene was perhaps first isolated from the berries of Tamus communis (Dioscorea communis, newer nomenclature) by a chemist, Frederik Anthony Hartsen, in 1873 [8]. Subsequently, in 1875, a botanist Alexis Millardet extracted it from tomatoes as a crude crystalline mixture and named it solanorubin. It was not until 1903 that chemist Carl A. Schunck identified this red pigment as distinct from other carotenoids and named it “lycopine”, likely deriving the term from the tomato’s botanical name, Lycopersicon esculentum [9,10]. It remains unclear how “lycopine” eventually became “lycopene” in common usage, which is now the standard nomenclature. Lycopene (PubChem ID 446925; MF: C₄₀H₅₆, MW: 536.9 g/mol) is a carotenoid characterized by its linear, acyclic structure composed of 40 carbon atoms forming a series of 13 double bonds, 11 of which are conjugated [11,12]. This extensive conjugated system imparts lycopene with its deep red colour and potent antioxidant properties [11,12]. This conjugated system allows lycopene to absorb light in the blue and green regions of the visible spectrum, with absorption maxima of around 505 nm. As a result, the remaining unabsorbed light is rich in red wavelength, which is reflected, giving lycopene its characteristic red colour. The number of conjugated double bonds in a molecule directly influences its colour (a greater number of these bonds shift absorption toward longer wavelengths, resulting in the reflection of colours like red). Unlike many other carotenoids, such as β-carotene, which possess cyclic end groups (rings) at both ends of their structures, lycopene lacks these terminal rings, resulting in its open-chain configuration [11,12,13]. Additionally, lycopene does not exhibit pro-vitamin A activity, distinguishing it functionally from carotenoids like β-carotene that can be converted into vitamin A in the human body.

Lycopene exhibits distinct pharmacokinetic properties in humans. Upon ingestion, lycopene is incorporated into lipid micelles in the small intestine, facilitated by dietary fats and bile salts. Absorption occurs primarily via passive diffusion and is mediated by scavenger receptor class B type 1 (SR-B1) [14,15]. Once absorbed, lycopene is transported through the lymphatic system within chylomicrons and subsequently distributed to various tissues, with notable accumulation in the liver, adrenal glands, and testes [16,17]. The compound undergoes extensive isomerization, predominantly converting from the all-trans form to cis-isomers, which are more bioavailable and preferentially accumulate in tissues [16]. Metabolism involves oxidative cleavage by enzymes such as β-carotene oxygenase 2 (BCO2), leading to the formation of polar metabolites, which are excreted in urine. Pharmacokinetic studies have reported single-dose administration (10 to 30 mg) in healthy human adult males, a time to reach maximum plasma concentration (0.08–0.21 µM) (Tmax) ranging from 15 to 33 h post-ingestion, with a half-life varying between 28 and 62 h and volume of distribution varying from 250 to 800 L, indicating prolonged retention in the body [16,18]. These parameters can be influenced by factors including the food matrix, presence of dietary fats, and individual variations in metabolism [16,18]. Understanding these pharmacokinetic characteristics is essential for optimizing lycopene’s therapeutic applications and determining appropriate dosing regimens.

Lycopene has gained significant attention for its broad spectrum of pharmacological activities. Its principal mechanisms of action include potent antioxidant, anti-inflammatory, and anti-proliferative effects, which collectively contribute to its therapeutic potential across a range of diseases in humans [7,19,20,21,22]. As a strong antioxidant, lycopene efficiently scavenges reactive oxygen species (ROS), thereby protecting cells from oxidative damage, a critical factor in the pathogenesis of cardiovascular diseases, cancers, and neurodegenerative disorders [7,19,20]. Lycopene modulates inflammatory responses by inhibiting pro-inflammatory cytokines and promoting negative feedback mechanisms that suppress chronic inflammation. This anti-inflammatory effect plays a vital role in conditions such as cardiovascular disease, where lycopene improves vascular function and reduces oxidative stress [23,24]. Neuroprotective effects have also been observed, with lycopene helping preserve cognitive function by mitigating oxidative damage and neuroinflammation in disorders like Alzheimer’s and Parkinson’s disease [25,26]. In cancer prevention, lycopene interferes with growth factor receptor signalling and cell cycle progression, particularly in prostate cancer cells, without inducing toxicity or apoptosis [7,19]. It also impacts pathways such as the mevalonate pathway and Ras activation, further supporting its antitumor activity [27]. In metabolic disorders, lycopene improves insulin sensitivity, lowers blood glucose levels, and protects pancreatic β-cells from oxidative stress, indicating benefits in diabetes and metabolic syndrome [28,29]. At the molecular level, lycopene interacts with a variety of human targets, modulating key signalling pathways including MAPKs, PI3K/Akt, and NF-κB [30,31]. It inhibits IκB kinase to suppress NF-κB signalling and activates PPARγ, a nuclear receptor involved in glucose and lipid metabolism [32,33,34]. Lycopene also influences EGFR and Protein Kinase C (PKC), affecting cell growth and gene expression [20,35,36]. Despite numerous studies highlighting the beneficial effects of lycopene, the precise molecular mechanisms and biological targets underlying its therapeutic actions still have considerable scientific gaps. Traditional pharmacological approaches have identified some pathways influenced by lycopene; however, a comprehensive, systems-level understanding of lycopene pharmacology is lacking. Network pharmacology, which integrates systems biology and computational tools, offers a holistic framework to elucidate the complex interactions between bioactive compounds and biological systems. By constructing and analysing networks of protein-protein interactions (PPIs), we can identify key molecular targets and pathways modulated by compounds like lycopene.

In this study, we employed network pharmacology methodologies to systematically explore the molecular mechanisms and biological targets of lycopene in humans. By integrating data from open-access databases, we identified lycopene-associated proteins and constructed a PPI network (based on hydrogen bond formation) to discern critical targets and pathways. Furthermore, molecular docking analyses were performed to assess the binding affinities between lycopene and its potential targets, providing insights into the compound’s pharmacological interactions. This comprehensive approach aims to bridge the gap between observational studies and mechanistic insights, thereby advancing our understanding of lycopene’s therapeutic potential and informing future research directions.

2. Materials and Methods

2.1. Identifying Targets of Lycopene

The chemical structure of lycopene (PubChem ID 446925) was identified in PubChem database, and its SMILES ID _{(CC(=CCC/C(=C/C=C/C(=C/C=C/C(=C/C=C/C=C(/C=C/C=C(/C=C/C=C(/CCC=C(C)C)\C)\C)\C)/C)/C)/C)C)} was input into the SwissTargetPrediction web-based tool (http://www.swisstargetprediction.ch/ accessed from 22 January 2023 to 30 January 2023) with a Homo sapiens species section to identify all potential targets of lycopene. The target class of the lycopene targets identified were assessed as a percentage of the total targets for all the targets and as well as the top 15 targets. The lycopene targets identified were cross-checked for validity in the UniProt database (https://www.uniprot.org/ accessed from 4 February 2023 to 15 February 2023), and their AlphaFold (if available) 3D structure was downloaded in PDB format. For the targets where the AlphaFold structure was not available, homology modelling as reported before was used to generate a 3D structure [37,38]. The affinity values of lycopene to its identified targets were assessed using AutoDock vina 1.2.0 as reported before for other ligand–receptor combinations [39,40].

2.2. Assessing the Targetability Potential of Lycopene Targets

To assess the targetability potential of all identified targets by lycopene, the concentration-affinity ratio (CA ratio) for each of the targets was calculated as described before [37]. The following plasma concentration range of lycopene, 75, 170, and 210 nM, was used for the CA ratio assessment based on the lycopene dose range of 10, 30, and 90 mg/day and its volume of distribution of 520 L [16]. The CA ratio of lycopene to all its identified targets is presented as a heatmap.

2.3. Evaluating Protein–Protein Interactions Between Lycopene Targets

To assess the protein–protein interactions between the lycopene targets, the 3D protein structure of the targets (PDB files) was imported into Chimera software (version 1.13.1) in pairs, and the number of hydrogen bonds (H-bond) formed between each pair of targets at a 10 angstorm (10Å) distance was evaluated. To assess functionally relevant protein–protein interactions, we employed a hydrogen bond-based network analysis. By evaluating H-bond formation within a 10 Å distance, we aimed to capture the physicochemical potential for direct molecular interactions among lycopene-targeted proteins, providing structural insight complementary to conventional gene-centric network approaches. The data of these interactions was inputted into a Microsoft Excel sheet, and a heatmap was generated using the conditional formatting colour scale tool to identify major networks. The networks of the lycopene targets were categorised into the following two group: (1) high interacting networks and (2) significantly interacting networks based on at least ten pairs of targets showing >8000 H-bond between them using the quartile logic. If a minimum of ten pairs of targets showed >15,000 H-bond between them, then the target was categorised to have significantly interacting networks. A Venn diagram was plotted using the list of (1) all targets, (2) targets with high interacting networks, and (3) targets with significantly interacting networks to illustrate the logical relationships between these three datasets.

2.4. Analysing Tissue-Specific Protein Expression of Lycopene Targets in Humans

All the identified targets of lycopene with affinity values below 1 µM were evaluated for their tissue-specific protein expression using the Human Protein Atlas (https://www.proteinatlas.org) database [37,41]. Of the six high-affinity targets identified, we could analyse only five targets, as the protein expression data of SLC6A5 was not available. The tissue-specific protein expression data of the five high affinity lycopene targets (MAP2K2, SCN2A, SCN3A, TOP2A, and TRIM24) were plotted using a Venn diagram to assess the logical relationships between the expression pattern of the targets and to identify if any specific tissue type is of preference for lycopene pharmacological effects.

3. Results

3.1. Categories and Specific Targets of Lycopene in Humans

The target prediction screening of lycopene showed 94 possible targets with affinities varying from 57 nM to 14 mM (Figure 1). A significant proportion of lycopene targets were nuclear receptors (37%) followed by Family A G protein-coupled receptors (GPCR 18%), while the rest of the target categories ranged from 2 to 8% (Figure 1). When only the top 15 targets of lycopene were analysed, six distinct target classes were identified. Among these, 40% were nuclear receptors, followed by G protein-coupled receptors (GPCRs) at 26.7%, erasers at 13.3%, and phosphatases, secreted proteins, and ligand-gated ion channels each comprising 6.7%. Twenty targets of lycopene were observed to have affinity values <10 µM, and of these twenty targets, the following targets showed affinity values <1 µM: MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24.

To assess the targetability of the lycopene targets, we looked at concentration-affinity (CA) ratios at the lycopene plasma concentrations of 75, 170, 210 nM, which was based on the dose rate of 10–90 mg/day in humans. The CA ratio analysis confirmed the feasibility of targeting the three targets MAP2K2, SCN2A, and SLC6A5 as their CA ratio was >1, while the rest of the lycopene target showed a CA ratio of <0.1, suggesting the affinity values of lycopene to these targets was ten-fold greater than the achievable plasma concentrations of lycopene.

3.2. Computational Analysis of Lycopene Targets

The protein–protein interaction (PPI) analysis of all lycopene targets indicated 32 high-interaction and 9 significant-interaction targets (Figure 2). Of the 32 high-interaction targets, 5 (TRIM24, GRIN1, NTRK1, FGFR1, and NTRK3) showed affinity values to lycopene under 10 µM, while among the 9 significant-interaction targets, only two (CHRNB4 and PIK3CD) showed affinity values to lycopene under 10 µM. The CA ratios of lycopene targets with affinity values < 10 µM ranged from 0.01 to 0.03. Most lycopene targets, in addition to showing low affinity values, had negligible PPI (<10 hydrogen bonds), suggesting these targets are not of relevance to the pharmacological effects of lycopene or may be indirectly regulated. Based on the PPI and affinity values, we observe the following three categories of lycopene targets: (1) targets with high affinity values (<10 µM; MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, TRIM24, P2RY12, SLC6A1, AURKB, SCN4A, GRIN1, NTRK1, PDGFRA, RXFP1, CHRNB4, PIK3CA, FGFR1, ABCC1, NTRK3, and PIK3CD), (2) targets with high network interactions (TRIM24, GRIN1, NTRK1, CHRNB4, FGFR1, NTRK3, PIK3CD, CLK4, RXRG, CYP2A6, GRK5, RXRA, RXRB, CLK1, NFKB1, MAPK1, PDGFRB, PIK3R1, CXCR4, GLRA1, NR1I2, NR3C2, NFE2L2, NAMPT, PRMT1, METAP2, NR4A1, ADAM10, VDR, HSD17B10, SPHK1, and APEX1), and (3) targets with both high affinity values and network interactions (TRIM24, GRIN1, NTRK1, FGFR1, NTRK3, CHRNB4, and PIK3CD) (Figure 2).

3.3. Expression Pattern of Lycopene Targets in Human Tissues

For the expression analysis of the lycopene targets in human tissues, we only looked at high-affinity targets with affinity values <1 µM, as these targets are most likely to be pharmacodynamically preferred. Hence, the targets MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24 were assessed for their tissue-specific expression pattern (Figure 3). As we selectively looked at protein expression pattern, SLC6A5 was excluded, as its protein expression data was still pending normal tissue annotation. Moreover, its RNA expression data was limited to the lung, spinal cord, cerebellum, pituitary gland, testis, and cerebral cortex tissues in humans with the number of transcripts per million (nTPM) value <1. The remaining five lycopene targets, except SCN2A (expressed in five tissue types) showed extensive tissue expression with MAP2K2 and SCN3A being widely expressed (Figure 3). MAP2K2, SCN3A, TOP2A, and TRIM24 were collectively expressed in 23 different tissues. MAP2K2, SCN3A, TOP2A, and TRIM24 were all expressed in seminal vesicle, bone marrow, adrenal gland, and cervix (Figure 3). SCN3A, TOP2A, and TRIM24 were collectively expressed in parathyroid gland only. SCN3A and TRIM24 were collectively expressed in smooth and skeletal muscles. MAP2K2 and TOP2A were collectively expressed in spleen only. MAP2K2, SCN2A, SCN3A, and TRIM24 were collectively expressed in caudate nucleus only. MAP2K2, SCN3A, and TRIM24 were collectively expressed in the thyroid gland, ovary, and salivary gland. MAP2K2 and SCN3A were collectively expressed in pancreas, epididymis, liver, soft, and adipose tissues. MAP2K2, SCN2A, and SCN3A were collectively expressed in the cerebellum, cerebral cortex, kidney, and hippocampus (Figure 3). SCN3A was exclusively expressed in heart muscle. High expression of MAP2K2 protein was observed in 21 different tissues, while high expression of SCN2A (cerebellum), SCN3A (cerebellum, caudate nucleus, and thyroid gland), TOP2A (testis, placenta, skin, lymph node, tonsil, and bone marrow), and TRIM24 (thyroid gland) was observed only in one or few tissues (Figure 3).

4. Discussion

This study provides a comprehensive computational pharmacology analysis of lycopene, revealing its multi-target interactions and potential pharmacodynamic actions in humans. Our findings highlight the importance of moving beyond conventional hub-centric network pharmacology approaches. While traditional analyses prioritize targets with extensive known interactions, this may overlook pharmacologically relevant proteins with high binding affinity but limited representation in curated databases. By classifying lycopene targets based on both binding affinity and network connectivity, we provide a more comprehensive framework that captures both structural relevance and biological context, particularly valuable for understudied natural compounds such as lycopene. The in-silico target prediction identified 94 candidate targets, with affinity values ranging from 57 nM to 14 mM, highlighting the broad spectrum of lycopene’s molecular mechanisms [20,30,42,43]. This is particularly not surprising considering the broad spectrum of health benefits reported following lycopene use [16,21,44,45]. Notably, nuclear receptors constituted the largest proportion (37%) of target classes, consistent with previous findings that carotenoids often modulate gene expression via nuclear receptor pathways [46,47,48]. GPCRs represented the second-largest category (18%), indicating lycopene’s potential to modulate signalling at the membrane receptor level as well. Focusing on the top 15 targets of lycopene, six distinct target classes were identified, dominated again by nuclear receptors (40%) and GPCRs (26.7%), which is again consistent with prior reports indicating lycopene’s ability to modulate transcriptional and signalling pathways involved in inflammation, metabolism, and cellular proliferation [6,35,42].

Among the 20 targets with sub-10 µM affinities, 6 targets (MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24) exhibited high-affinity binding (<1 µM), suggesting these targets are most likely to be pharmacologically modulated at physiological concentrations of lycopene. While lycopene is known for its weak direct activity at most proteins due to its hydrophobic nature and limited aqueous solubility [49,50], our concentration-affinity (CA) ratio analysis provided a critical pharmacodynamic context. While lycopene’s bioavailability is limited under typical dietary intake, studies have shown that chronic supplementation or the use of bio-enhanced formulations can lead to its accumulation in tissue-specific niches such as the prostate, liver, and adrenal glands [51,52]. Our analysis focused on identifying pharmacologically relevant protein targets and interaction thresholds, thereby providing a mechanistic basis for lycopene’s potential therapeutic effects under conditions of sustained or optimized exposure. Only three targets (MAP2K2, SCN2A, and SLC6A5) showed CA ratios > 1 at reported human plasma concentrations (75–210 nM), suggesting these are the most pharmacologically viable targets under physiological conditions. While compounds with CA ratios > 1 are more likely to exert biological effects at attainable plasma levels, considering previous studies indicating that lycopene exerts biological activity at nanomolar concentrations [53,54,55], particularly within membrane-rich environments or lipid rafts where its accumulation is higher [56,57], it is likely that other lycopene targets with CA ratios < 1 can potentially be involved in its pharmacodynamic effects.

Protein–protein interaction network analysis further identified a subset of targets with significant biological relevance. We identified 32 high-interaction and 9 significant-interaction proteins, with some of these targets (TRIM24, GRIN1, NTRK1, FGFR1, and NTRK3) exhibiting binding affinities below 10 μM. Although their CA ratios remained low (<0.03), these targets may act as secondary effectors or are relevant in tissues with higher lycopene accumulation, such as the prostate, liver, and adrenal glands [16,52]. TRIM24, GRIN1, NTRK1, FGFR1, NTRK3, CHRNB4, and PIK3CD are key proteins with diverse biological roles, many of which are relevant to disease pathogenesis and potential pharmacological targeting [58,59,60]. TRIM24 is a transcriptional co-regulator that modulates nuclear receptor signalling and chromatin remodelling. It plays a critical role in cell proliferation and apoptosis and has been implicated in the development of several cancers, particularly breast and liver malignancies [61,62]. GRIN1 encodes a core subunit of NMDA receptors essential for calcium ion influx during synaptic transmission. It is central to learning, memory, and neural development, and its dysregulation is associated with neurodegenerative diseases consequence to excitotoxicity [63,64]. Alterations in NTRK1 is linked to various cancers and sensory disorders, while NTRK3 is associated with breast carcinoma and congenital fibrosarcoma [65,66]. FGFR1, by mediating pathways involved in growth, angiogenesis, and tissue repair, contributes to developmental syndromes and several cancers, while CHRNB4 is critical for synaptic transmission in the nervous system and is implicated in neurological conditions such as epilepsy, schizophrenia, and nicotine dependence [67,68,69]. PIK3CD is predominantly expressed in immune cells and regulates pathways central to immune function, and its mutations are associated with primary immunodeficiencies like Activated PI3K-Delta Syndrome [70]. Hence, PIK3CD is a target of interest in autoimmunity and cancer therapy. These novel observations in our study on the diverse pathophysiological role of lycopene targets identified are consistent with several clinical investigations and reports on the potential use of lycopene for healthcare [21,71,72].

Expression profiling of the highest-affinity targets provided further insight into the tissue-specific pharmacodynamics of lycopene. Except for SLC6A5, whose protein expression data is unavailable, the remaining high-affinity targets showed expression in a range of tissues. MAP2K2, SCN3A, TOP2A, and TRIM24 are functionally involved in oncogenic signalling, neuronal excitability, and DNA repair, offering diverse but interconnected avenues for pharmacological intervention. Particularly, MAP2K2, SCN3A, TOP2A, and TRIM24 were co-expressed in reproductive and endocrine tissues (seminal vesicle, adrenal gland, and cervix). These results are consistent with past transcriptomic studies that observed the upregulation of lycopene-responsive genes in prostate and mammary tissues [57,73,74]. Consistent with our observation, a recent study also demonstrated MAPK pathway to be a target of lycopene in alleviating renal ischemia-reperfusion injury in an animal model [34]. MAP2K2 is a critical component of the MAPK/ERK signalling pathway, which regulates cell proliferation, differentiation, and survival. Aberrant activation of MAP2K2 has been linked to various cancers, particularly melanoma and colorectal cancer, making it a validated target for anti-cancer therapies [75,76]. The pharmacological inhibition of MAP2K2 has shown potential in overcoming resistance to upstream oncogenes such as BRAF and RAS, and it remains to be tested if lycopene can have synergistic effects with these established MAP2K2 inhibitors to achieve optimal pharmacodynamic outcomes while minimising any potential adverse effects. Interestingly, SCN3A, a voltage-gated sodium channel, showed unique expression in the heart, pointing to possible roles in cardiac excitability, supporting prior studies reporting cardiovascular benefits of lycopene via electrophysiological and anti-inflammatory mechanisms [77]. SCN3A is predominantly expressed in the central nervous system, where it is essential for the initiation and propagation of action potentials in neurons. Dysregulation or mutations in SCN3A are associated with neurological disorders including epilepsy, developmental and epileptic encephalopathies, and cognitive impairments. SCN3A represents a target for anticonvulsant development and therapies aimed at modulating neuronal excitability [78,79]. Based on our findings, there seems to be merit in assessing the potential of lycopene in connecting the heart–brain axis via SCN3A targeting. TOP2A and TRIM24 have a vital role in DNA replication, transcription, and chromosome segregation and are well-established targets in cancer chemotherapy especially in breast, prostate, and liver cancers [80,81]. Our report of the high-affinity targeting of TOP2A and TRIM24 opens avenues for synergistically improving the pharmacodynamics of currently used chemotherapeutics (etoposide and doxorubicin) with lycopene.

While this study provides a comprehensive computational analysis to identify potential targets of lycopene, it is important to note that the findings are primarily based on in silico predictions. Although tissue expression and pharmacokinetic properties were considered to enhance biological plausibility, experimental validation such as an in vitro or in vivo study was beyond the current scope. This represents a key limitation, and future studies are necessary to empirically validate the predicted targets and elucidate their mechanistic roles in lycopene’s biological activity. Additionally, the use of CA ratios is based on simplified pharmacokinetic assumptions and does not capture the dynamic nature of biological systems; as such, these estimates should be interpreted as preliminary indicators rather than definitive measures of pharmacodynamic feasibility.

Collectively, our findings suggest MAP2K2 and SCN2A as the most pharmacodynamically plausible direct targets of lycopene in humans. Their strong affinity, favourable CA ratios, and wide tissue expression profiles suggest that these targets have a foundational role in mediating lycopene’s pharmacological actions. Additional targets such as TRIM24, TOP2A, and NTRK family members, while displaying lower CA ratios, may contribute to lycopene’s broader systems-level impact, particularly in the context of inflammation, cancer biology, and neuroprotection. These multi-target interactions are consistent with lycopene’s observed pleiotropic benefits in clinical and preclinical models [7,30,37,45,82].

In conclusion, our study advances the mechanistic understanding of lycopene pharmacology by integrating affinity profiling, network analysis, and expression mapping. While the hydrophobicity and relatively low systemic concentrations of lycopene pose challenges for classical drug-likeness, its selective interaction with key signalling and nuclear proteins highlights its potential as a nutraceutical agent with systems-level effects, which merits advancing its use for therapeutic applications. Future studies should aim to validate these interactions in functional cellular assays and assess tissue-specific accumulation patterns to better delineate lycopene’s therapeutic potential.