Plant protein-phenolic acids as novel food-grade synergistic modulators of neuronal function: A review

Abstract

With modernization, changing lifestyles, and the accelerating pace of global aging, addressing issues such as emotional instability, high incidence of neurodegenerative diseases, and cognitive decline has become paramount. When plant proteins and phenolic acids act independently on neurons, their promotional effects remain relatively limited. However, upon interacting through non-covalent and/or covalent bonds, the spatial structure of plant proteins undergoes alteration, providing key precursors for neurotransmitters. Encapsulated within the plant protein structure, phenolic acids exhibit significantly enhanced stability, enabling more effective neuroprotective functions. Their synergistic action promotes neurotransmitter release while simultaneously activating key signaling pathways, regulating gut microbiota, and generating neuroactive metabolites. This establishes a crucial foundation for further exploration in neuronal regulation and functional food development.

Graphical abstract

Highlights

• •Protein-phenolic acid synergism boosts single-component functionality.
• •Covalent complexes better regulate protein structure and nerve function.
• •The complex regulates neuronal secretion via gut-brain axis & amino acid metabolism.
• •Positive effects of complexes on neuronal function and prevention of related diseases.

1. Introduction

In today's high-pressure social environment, mood disorders are highly prevalent, and it is estimated that 3.8 % of the world's population suffers from depression, 7.3 % suffers from anxiety disorders, and 0.79 % suffers from autism, so the stability of the neuronal secretion system has become a critical line of defense in sustaining human emotional health (Wang, Brennan, et al., 2022). Traditional pharmacological treatments are widely used in clinical practice, such as antidepressants, anxiolytics, and dopamine agonists (Daftari & Tritos, 2025). Dopamine agonists directly stimulate dopamine receptors and exert dopamine-like effects, but have significant side effects, including nausea, vomiting, drowsiness, and impulse control disorders (Martins et al., 2021). In the face of the constant stimulation of chronic stress, information overload and social anxiety, the exploration of safe and sustainable dietary intervention strategies has become a common focus of attention for both science and industry. Meanwhile, the intersection of functional ingredient research with neurobiology and other disciplines in the field of food nutrition is becoming increasingly promising. However, the emotional problems caused by the imbalance of neurotransmitters and other chemicals in the brain still need to be studied and discussed (Matiș et al., 2023). Therefore, in this paper, the protein-phenolic acid interaction is used to stimulate neuronal secretion, which in turn modulates the neurotransmitter system.

With the growing awareness of the relevance of quality protein in the diet, this has encouraged researchers and nutritionists to look for environmentally friendly and sustainable sources of protein (Pojić et al., 2018). Plant proteins, as a core resource for replacing animal proteins, have functional properties (e.g., amino acid composition, release of bioactive peptides) that are closely related to neurological health. In the last decade, there has been a significant increase in applications for plant proteins (Sá et al., 2020). Plant proteins are mainly found in legumes (soybeans, peas, chickpeas, lentils, black beans, red beans), cereals (wheat, rice, oats, maize), nuts and seeds (peanuts, chia seeds, sunflower seeds), algae (spirulina, alfalfa leaf proteins), tubers and roots (potatoes, cassava) (Hadidi et al., 2022). Compared to animal proteins, plant protein is rich in dietary fiber, low in fat, and virtually cholesterol free. It is suitable for vegetarians, lactose intolerant or allergic to animal proteins, and is an important way for special populations to obtain protein. During application, plant protein produces relatively low greenhouse gas emissions and has a low environmental impact, which is green and sustainable and helps to maintain the stability of the ecosystem (Kim et al., 2024). Some essential amino acids in plant proteins are raw materials for neurotransmitter synthesis. For example, tryptophan—found in legume-based plant proteins—is a precursor to serotonin. As an important neurotransmitter, serotonin influences neuronal secretion and transmission, and plays a key role in physiological functions such as mood regulation and sleep. Leu-Ser-Ser-Thr-Gln-Ala-Gln- Leu-Ser-Ser-Thr-Gln-Ala-Gln-Gln-Ser-Tyr is a decapeptide derived from the α and β subunits of β-associated soybean globulin, which can be released from soybean β-associated soybean globulin by pyrolytic enzyme digestion. Y. Zhang et al. (Zhang, Lu, et al., 2025) reported that after oral administration of this soybean-derived peptide at a dose of 0.3–3.0 mg/kg to ddY and C57BL/6 J mice, the resting time of the mice was shortened in the tail-suspension test (TST) and forced-swimming test (FST) and they showed antidepressant-like effects.

Phenolic acid is a class of compounds containing multiple phenolic hydroxyl groups in the molecular structure (Quan et al., 2019)， which as a secondary metabolite of plants is a phytochemical with beneficial effects on health (Welc-Stanowska et al., 2023)， and possesses antioxidant, anti-inflammatory, and cardiovascular disease preventive effects, and improves the neuron microenvironment, indirectly affecting Neurotransmitter synthesis and secretion. It can also improve mood and cognitive function by regulating related enzyme activities, activating neurotrophic factors, influencing cell signaling, and supporting neuronal health and synaptic plasticity. For example, chlorogenic acid (CGA) inhibits oxidative stress, attenuates neurotoxicity induced by Aβ25–35, increases cellular antioxidant capacity, significantly improves spatial memory impairment, and attenuates CA1 neuronal damage in the hippocampus. (Li, Wei, et al., 2024). Gallic acid (GA) significantly reduces Aβ1–42-induced intracellular calcium ion influx, suggesting that it may attenuate neurotoxicity by decreasing calcium ion influx through reducing Aβ aggregation. (Yu et al., 2019). However, the chemical properties of phenolic acid are relatively unstable, and it is easy to have neutralization reactions with bases, the phenolic hydroxyl group is easily oxidized, and the hydrogen atom on the benzene ring becomes more active under the influence of the hydroxyl group. Moreover, the low uptake rate and slow target delivery efficiency to organs, tissues and cells have limited the application of phenolic acids (Li, He, et al., 2021).

In contrast, the complex formed by dynamic binding of plant proteins and phenolic acids cannot only overcome the limitations of a single component, such as low protein solubility and poor stability of phenolic acids, but also synergistically regulate the neurotransmitter secretion pathway. Plant proteins and phenolic acids can alter plant protein solubility (Can Karaca et al., 2025)， and improve phenolic acid stability, antioxidant activity, bioavailability. For example, CGA was added to sunflower protein solution to evaluate the extent of protein modification, physicochemical properties, solubility, and gelling capacity of the solution in noncovalent and covalent interactions at pH 7 and pH 9, respectively. Both modes of binding of CGA to proteins have a positive effect on protein solubility (Jia et al., 2022a). Phenolic acids can bind to plant proteins through hydrogen bonding, π interactions, hydrophobic interactions, metal coordination, electrostatic interactions, and covalent bonding, resulting in altered intramolecular or intermolecular forces that lead to structural rearrangements of the protein. Both interactions also alter the physical and chemical properties of phenolic acids, thereby protecting them from oxidation and enzymatic degradation and activating neurotrophic factors that support neuronal health and synaptic plasticity (Li, He, et al., 2021).

How synergistic effects directly influence neurotransmitter pathways and regulate mood remains an area lacking systematic review and critical evaluation. Existing research predominantly focuses on the physicochemical properties of these complexes while neglecting their overall physiological functions, particularly the synergistic mechanisms affecting brain emotions. Therefore, against the backdrop of growing public interest in functional foods and mental health, a timely review of their synergistic neuromodulatory effects holds significant importance for revealing their application potential and guiding future research directions. Plant protein-phenolic acid interactions indirectly affect neuronal secretion of neurotransmitters such as dopamine, serotonin, and endorphins through a variety of mechanisms (Hodo et al., 2020), and both enhance neurotransmitter production and release by reducing oxidative stress, increasing the release of neurotransmitter precursor amino acids, and regulating gut flora (Williamson & Clifford, 2025). The synergistic effect of both helps to enhance pleasure, stabilize mood and alleviate anxiety and depression, thus positively affecting mood.

This review focuses on the functional effects of plant protein-phenolic acid interactions on human absorption and mood changes through different forms of interactions, as well as the mechanism of the two interactions on mood changes, providing a strategy for engineering plant protein-phenolic acid interactions for more functional applications.

2. Plant proteins from different food sources

Plant proteins have become one of the most popular and environmentally friendly substances among consumers today. Among them, highly soluble plant proteins are more easily digested and absorbed by the human body (He et al., 2021), providing essential amino acids for neurons to synthesize neurotransmitters and other necessary compounds. After digestion and absorption, plant proteins break down into amino acids that serve as building blocks for various enzymes involved in metabolism and growth. They also function as signaling molecules and hormones to maintain physiological pH levels and support the immune system (Kumar et al., 2022). Research has also shown that the intake of amino acids can regulate synaptic plasticity and reduce damage to nerve cells (Polyiam & Thukhammee, 2024b). Encapsulation serves as an effective alternative strategy for protecting bioactive substances and enhancing functional food development. Bioactive substance encapsulation technology has garnered significant attention due to its high protective efficacy, targeted release capabilities, improved solubility and stability, and ability to mask undesirable flavors (Hadidi et al., 2023). Plant proteins, with their excellent emulsifying and gelling properties, biocompatibility, amphiphilicity, and non-toxicity, represent promising carrier options. Proteins have various functional groups and can easily interact with natural bioactive compounds to form nanocarriers (Venkidasamy et al., 2025)， thereby altering the amino acid sequence, isoelectric point, secondary or tertiary structure, as well as their physicochemical properties and biological activities, including solubility, hydrophobicity, hydrophilicity, thermal stability, digestibility, and antioxidant capacity (Masoumi et al., 2024).

2.1. Cereal proteins

Gluten proteins are found in cereals, such as wheat, rice, corn, and barley, and are important nutrients and functional components of cereals (Jiang et al., 2022). Rice glutenin is a cereal protein with high nutritional value, hypoallergenic properties, and hypocholesterolemic effects. It is also the main storage protein in rice, accounting for 60–80 % of total rice protein. This protein mainly consists of two polypeptide subunits: the acidic subunit α chain and the basic subunit β chain. α chain has a molecular weight of about 30–39 kDa and contains more acidic amino acids, such as glutamic acid, while β chain has a molecular weight of about 19–22 kDa, and contains more basic amino acids, such as arginine. α and β chains are covalently linked by disulfide bonds, and together they form a complex polymer (Amagliani et al., 2017). Rice glutenins are highly insoluble in water due to extensive cross-linking and aggregation through disulfide bonds and tend to have more hydrophobic groups in their internal structure. Y. Li et al. (Li, Wang, et al., 2022) dissolved rice glutenin in a solution at pH 12 and heat-treated it at 121 °C for 20 min. It was found that the solubility of rice glutenin increased from 2.55 mg/mL to 20.7 mg/mL and the molecular size decreased from 900 nm to 400 nm at pH 7. This was mainly attributed to the high temperature treatment-induced decrease in glutenin aggregates, conformational unfolding, and changes in tyrosine and tryptophan residues, which led to the enhancement of solubility.T. Li et al. (Li, Wang, et al., 2021) experimentally investigated the self-assembly and structural changes of rice glutenin when the heating time was varied, during which the structure of glutenin was rearranged and accompanied by elongation and nucleation stages, which resulted in the formation of fibers with a maximum length of 843 nm. It is demonstrated that the stability of fiber structure depends on the dynamic balance of intermolecular positive electrostatic repulsive forces, and the hydrogen bonding between aromatic groups and π-π stacking effect promotes the rearrangement of fiber structure, which can optimize the experimental conditions to improve the functional properties of glutenin.

Zein is an alcohol-soluble storage protein (Wang, Chen, et al., 2024).It exists in the proteasomes within the maize endosperm and on the surface of starch granules, and accounts for 44–79 % of total maize proteins (Peng et al., 2024; Wang, Li, et al., 2022) Additionally, zein possesses good biocompatibility and bioadhesion properties. Because of the relatively large proportion of polar amino acids in zein, they can be self-assembled into particles or nanoparticles by changing the solubility. Zein can be classified into four different fractions based on differences in solubility: α-, β-, γ-, and δ-zein (Can Karaca et al., 2025; Dong et al., 2020). Among them, α-zein accounts for about 70 % of the total zein, which is subject to hydrogen bonding between hydroxyl and imino groups on the peptide main chain to form an α-helical secondary structure. β-zein has higher levels of histidine, arginine, proline, and methionine, and contains a high number of disulfide bonds, which gives the structure a certain degree of stability and flexibility. Commercial zein consists mainly of α-zein and contains a small amount of β-zein (Zhang et al., 2021). Zea mays zein molecules can self-assemble into nanoparticles to capture bioactive substances. Zein nanoparticles have been demonstrated to significantly enhance the antioxidant activity of thymol and carvacrol (Wu et al., 2012), achieve high encapsulation efficiency for eugenol (Luis et al., 2020), and enable controlled release of gamma-oryzanol (Rodsuwan et al., 2021). Additionally, this structure can form a stable complex with phenolic acids, which controls the rate of release of the bioactive substance phenolic acids through disulfide bond breaking and rearrangement, facilitating a slow release in the intestinal tract and allowing the body to fully utilize it. Studies on the interaction of zein with phenolic acids have attracted increasing attention. Q. Wang et al. (Wang, Tang, et al., 2022b) found that after interacting zein with ferulic acid(FA), FA protected the hydrophobic sites in zein and affected the interfacial properties of zein, which could modulate the stability of food formulations such as foams and emulsions.

2.2. Legume proteins

Mung beans are an important source of high-quality protein and phytochemicals. Pontapan Polyiam and others (Polyiam & Thukhammee, 2024b) studied the amino acid profiles of plant proteins as well as the antioxidant and neuroprotective activities from cashew, mung bean, mulberry leaves, Lagerstroemia species, and sunflower sprouts. They found that mung bean protein has high levels of essential amino acids and dietary fiber, both of which are higher than those in sunflower sprouts, Lagerstroemia, cashew, and mulberry leaf proteins. The most abundant amino acid, arginine, can regulate synaptic plasticity. Among legume proteins, pea protein is hypoallergenic and highly digestible (Kim et al., 2025)， which is rich in lysine and helps to promote human development, enhance immune function, and improve the function of central nervous tissue. Pea protein consists of a polypeptide chain of approximately 638 amino acids linked linearly by peptide bonds. The polypeptide chain consists of α-helices, β-folds, and β-turns, of which the α-helices and β-folds form a stable and compact structure through hydrogen bonding (Othmeni et al., 2025). Gonzalez et al. (González et al., 2021) summarized that the content of β-sheets was significantly reduced when the drying temperature was changed from 50 to 70 °C, and the protein digestibility was increased from 76.26 % to 85.87 %. This is due to the exposure of cleavage sites on the protein, which destroys the rigid structure such as β-sheets. The infrared spectra also showed an increase in β-sheet aggregates, which was analyzed that this could be due to protein-protein hydrophobic interactions and covalent bond formation, which contributes to the construction of the protein gel network. In legume pea proteins, they can be mainly classified into 2S, 7S, 11S, and 15S globular proteins according to the sedimentation coefficient (Gan et al., 2016). 7S globular protein aggregates form larger particles in solution through non-covalent interactions such as hydrophobic interactions, electrostatic interactions, and other non-covalent interactions, which are not easily dispersed in water, which reduces the water solubility of the protein (Stojadinovic et al., 2013). 11S globulin is the main component of pea proteins with a similar content to 7S globulin, which consists of acidic subunits and basic subunits through disulfide bonds, and has poor water solubility due to the rigid structure of the subunits. Research indicates that when pea protein interacts with resveratrol, the water solubility of resveratrol increases by nearly 1000-fold, and its biological activity is also enhanced (Tang et al., 2026).

2.3. Seed proteins

Hemp seed proteins are by-products of hemp seed oil production and can be recovered from the press cake, which contains the psychoactive substance tetrahydrocannabinol (Kutzli et al., 2023). Hemp seed proteins have a good amino acid composition with high levels of arginine and glutamine (Li, Zhang, et al., 2022). However, they are in an inactive state in the parent protein and after the hydrolysis process, they have been shown to have beneficial effects on human health such as antioxidant, antihypertensive, hypoglycemic, and hypolipidemic effects. Guillermo Santos-Sánchez et al. (Santos-Sánchez et al., 2022) reported that hemp seed proteins were exposed to a high concentration of alkaline proteases at 50 °C, pH 9.4. After interacting with alkaline protease for 1 h at 50 °C and pH 9.4, it was found that hydroxyl radical scavenging activity, superoxide radical scavenging activity, and DPPH radical scavenging activity were increased. The poor solubility of cannabis seed proteins, on the other hand, is due to the high content of sulfur amino acid residues in their structure, which makes it easy to form disulfide bonds between molecules, thus increasing the degree of protein aggregation (N. Wang, Wang, et al., 2025). Furthermore, in the experiment on the effect of defatting process on the structural properties of cannabis seed proteins, it was found that the secondary structure of cannabis seed proteins was mainly dominated by β-sheets, followed by α-helices, β-turns and random curls. While the presence of β-sheets provides a rigid structure for hempseed protein, which also limits its solubility (Fang et al., 2023). Xu et al. (Xu et al., 2024) investigated the interactions between hemp seed globulin and two hemp seed phenolic compounds. The results indicated that the secondary structure and particle size of hemp seed globulin were consistently influenced by interactions with both phenolic compounds. Compared to untreated hemp seed globulin, phenolic compound-treated hemp seed globulin exhibited higher ABTS and DPPH scavenging capacities as well as improved digestibility.

3. Plant protein-phenolic acid interactions

After the structural characteristics of plant proteins from different food sources lay the foundation for their interaction with phenolic acids, the key link between ‘raw material properties’ and ‘neural regulation effects’ lies in how plant proteins and phenolic acids specifically bind, how their structures change after binding, and what functional enhancements result. Plant protein-phenolic acid complexes are formed through non-covalent or covalent interactions (Welc-Stanowska et al., 2023)， and their binding has a great role in nutritional health, food production, and biological activity (Dai et al., 2024). Phenolic acids are chemically unstable, and plant proteins can protect phenolic acids by forming spatial site barriers that encapsulate phenolic acids internally or adsorb them on their surfaces, reducing their exposure to oxidizing factors such as oxygen, light, and metal ions (Li et al., 2025). Phenolic acids as antioxidants provide phenolic hydroxyl groups that neutralize free radicals by releasing hydrogen atoms, thereby reducing their reactivity by leaving the unpaired electrons on the phenoxy ring (Marković & Tošović, 2016). Phenolic hydroxyl groups cause changes in the spatial structure of plant proteins, exposing binding sites that would otherwise be hidden within the protein and facilitating further binding between the two. For example, the polyphenolic substance tannic acid, which is formed by the combination of both polyols and GA or hexahydroxydiphenic acid, is a phenolic substance with large molecular weight and hydroxyl groups, and has a strong binding affinity with proteins because it exposes the hydrophobic sites of proteins and has a high content of hydroxyl groups (S. Wang, Wang, et al., 2025)， and can improve the stability, viscosity, and bioactive substances such as curcumin, etc., in soybean protein-based emulsions. and the release rate of bioactive substances such as curcumin (Song et al., 2024).Whitman et al. (Ma et al., 2025) in their report on the covalent binding of CGA to soy protein (SPI) to form hydrogels mentioned that DPPH and ABTS free radical scavenging activities were increased by 30.29 % and 40.69 %, respectively, on the addition of CGA (0.01 g/g-SPI). As shown in Table 1, the plant protein-phenolic acidinteraction not only improves the antioxidant activity of phenolic acid, effectively scavenges free radicals and reduces neuronal cell damage by oxidative stress, but also improves solubility, emulsifying property, and stability of plant proteins. Vanessa Soendjaja et al. (Soendjaja & Girard, 2024) found that the off-flavors in plant products such as beans are mainly related to lipid oxidation, production of volatile compounds, and the addition of phenolic acids can reduce the soya and grassy flavors in plant proteins, and this reaction process depends on the conditions under which the coupling occurs.

Plant proteins and phenolic acids mainly combine through non-covalent interactions and covalent interactions. The non-covalent bonding between them is reversible, usually occurring under mild conditions and dominated by weak interactions, including hydrogen bonding, hydrophobic interactions, and electrostatic interactions (Welc et al., 2022). Because these forces are relatively weak, the aggregation is relatively loose, making it easily degradable by gut microbiota (Li, Kang, et al., 2024), thereby optimizing gut microbiota structure to regulate neuronal function. Covalent bonding is an irreversible interaction, usually involving oxidative coupling or enzyme-catalyzed crosslinking (Hao et al., 2022).Its covalent bonding stability is extremely strong, and such strong chemical bonds can only be broken under specific enzymatic hydrolysis or chemical conditions. This results in a gentler release rate and a longer release cycle of phenolic acids (Shi et al., 2024), thereby enhancing the sustainability of the neuroactive effects of phenolic acids. The formation of complexes between plant proteins and phenolic acids is influenced by pH (Wang, Lan, et al., 2024), temperature, and the type of enzyme (Du et al., 2022). pH affects the isoelectric point (pI) of plant proteins and the dissociation state of phenolic acids, thereby directly influencing the electrostatic interaction between the two. Qiming Wang et al. (Wang, Tang, et al., 2022) investigated the interaction mechanism between zein and FA under different pH conditions, and the results showed that changes in pH value are a crucial factor affecting the binding affinity between the two, with their binding stability under alkaline conditions being stronger than that under acidic and neutral conditions. Lloyd Condict et al. (Condict et al., 2019) reported that covalent complexes formed during ultra-high-temperature instant sterilization exhibit significantly higher stability than those formed at lower temperatures, along with greater resistance to pepsin. Studies indicate that the cumulative release rate of FA over 24 h in ultra-high-temperature instant sterilized oat-milk protein complexes is reduced by more than 30 % compared to non-ultra-high-temperature instant sterilized groups. Laccase is a polyphenol oxidase that catalyzes the oxidation of phenolic acids into quinones (Li, Kang, et al., 2024). Quinones readily undergo nucleophilic reactions with protein amines, promoting the formation of covalent complexes. Additionally, the enzyme can hydrolyze, cross-link, or glycosylate plant proteins, altering their molecular weight and the number of surface active sites, thereby regulating their binding capacity to phenolic acids (Wang, You, et al., 2022b).

3.1. Reversible interactions

Polar groups such as hydroxyl and carboxyl groups of phenolic acids can form hydrogen bonding network structures with amino, carboxyl or hydroxyl groups in plant proteins. Li Xin et al. (Li et al., 2023) analyzed the interaction mechanism between SPI and tannic acid in oil-in-water emulsions, combined with thermodynamic parameter theory. They found that when ΔH < 0 and ΔS < 0, hydrogen bonding interactions are the dominant force. At a temperature of 310 K, the ΔH of SPI and tannic acid in oil-in-water emulsion was −78.31 ± 4.71 and ΔS was −0.14 ± 0.02, and the results indicated that the two were mainly bonded by hydrogen bonding in non-covalent bonds. Zhu et al. (Zhu et al., 2024) explored the interaction mechanism between SPI protofibers and CGA and found that the glutamine residues of SPI and the o-diphenol hydroxyl group of CGA were bonded through hydrogen bonding, and the addition of CGA in the pre-interaction period caused a change in the flexible conformation of SPI due to the formation of the hydrogen bond. When the amount of CGA is gradually increased, the two bindings reach saturation, and the optimal structural state occurs when the concentration ratio of CGA to SPI is 0.05, showing better antioxidant activity. In the molecular structure of plant proteins, there are some regions composed of nonpolar amino acids such as alanine, valine, leucine and so on. The side chain groups of these non-polar amino acids do not have ionizable polar groups and they are hydrophobic. During protein folding, in order to avoid surrounding water molecules, these hydrophobic regions accumulate inside the protein, forming a relatively hydrophobic microenvironment (Hashemi et al., 2025). When plant proteins bind to phenolic acids, the hydrophobic parts of phenolic acids such as benzene rings and carbon chains will tend to enter the hydrophobic microenvironment inside the proteins to reduce the contact area with water molecules. The hydrophobic regions of plant proteins and phenolic acids are attracted to each other through weak interactions such as van der Waals forces, resulting in hydrophobic interaction. Gan Jing et al. (Gan et al., 2016) also demonstrated experimentally that hydrogen bonding and hydrophobic interactions are the main driving forces between SPI 7S and phenolic acids. In the fluorescence spectra of SPI 7S with the change of concentration in the absence and presence of coumaric acid, caffeic acid (CA), GA, and CGA at pH 7, it was found that different fluorescence intensities at 415–425 nm appeared when each of the four phenolic acids bound to SPI 7S, and the fluorescence intensity of SPI 7S decreases with the increase of the concentration of the phenolic acids, and the fluorescence quenching degree when the concentration of the four reached 60 uM was 90 %, 93 %, 95 % and 91 %. Since its fluorescent group molecules are quenched by diffusive collisions or by binding to the quencher in the ground state to form complexes (Stojadinovic et al., 2013)， which results in the disruption of the tertiary structure of SPI 7S, the phenolic acid interacts with SPI 7S in a structure-dependent manner.

Shu et al. (Shu et al., 2025) investigated the mechanism of non-covalent interaction between rice protein and different concentrations of FA and GA. FA and GA bind to rice protein through static bursts, and the bursts are of static nature, dominated by hydrophobic forces to bind to rice protein to form non-covalent complexes. The analysis revealed that the maximum emission peak of rice protein continued to redshift with increasing FA ratio from 354.4 nm to a final jump to 412.8 nm, in addition, the incorporation of GA led to a redshift of the peak of the protein, further suggesting that the exposure of tryptophan and tyrosine residues is due to protein defolding and binding to phenolic acids resulting in exposure to a more polar environment. The non-covalent binding of rice protein to the two phenolic acids significantly enhanced the ABTS radical scavenging and FRAP reduction capacities of rice protein, and emulsions stabilized by rice protein complexed with the two phenolic acids exhibited excellent oxidative stability compared to the pure proteins, and such interactions have been used as a strategy to improve the antioxidant efficiency of plant proteins.

Plant proteins are usually charged on the surface (Wu et al., 2025) and their properties depend on the pH of the solution and the isoelectric point of the protein. Phenolic acids, on the other hand, usually exist in anionic form due to the presence of phenolic hydroxyl and carboxylic acid groups. When the solution pH is lower than the isoelectric point of plant proteins, the surface of proteins shows positive charge, at which time binding with negatively charged phenolic acid molecules can occur through electrostatic attraction. Zhou et al. (Zhou, Wang, et al., 2023) investigated the non-covalent interaction mechanism of soybean 7S globulin with GA, CGA and EGCG, respectively. The interaction of soybean 7S globulin with GA is mainly affected by electrostatic interaction.GA is a small molecule phenolic acid containing several hydroxyl groups (-OH) and one carboxyl group (-COOH) in its molecular structure. Under neutral or alkaline conditions, the carboxyl group of GA dissociates to form a negatively charged carboxylate ion (-COO-).7S globulin has a variety of positively charged amino acid residues on its surface, such as lysine and arginine, which contain protonatable amino groups (-NH₂) in their side chains, which are normally protonated to form positively charged -NH₃⁺ groups, and thus the surface of 7S globulin carries a certain positive charge. The presence of negative charges in GA allows electrostatic interactions with positively charged protein amino acid residues. The electrostatic interaction enhances the binding force between the protein and phenolic acid, thereby increasing the stability of the protein. This stability helps to maintain the structural and functional properties of proteins during food processing and storage, preventing denaturation or degradation of proteins.

3.2. Irreversible interactions

As shown in Fig. 1, the irreversible covalent interactions are not only stronger and longer-lasting than the reversible non-covalent interactions, but also show better thermal stability, antioxidant activity and bioavailability (Zhou, Wang, et al., 2023). Covalent reactions between proteins and phenolic acids require alkaline conditions or the involvement of enzymes (Ma et al., 2025). Under alkaline conditions, phenolic acids in plant protein-phenolic acid covalent interactions are oxidized to the corresponding quinones radicals that irreversibly interact with amino and sulfhydryl groups on their protein side chains and ultimately react with nucleophilic groups in proteins to form C—N or C—S covalent bonds (GopikaJayaprakash et al., 2023). (See Table 1.)

Fig. 1.

Comparison of non-covalent and covalent interactions between SPI and CGA and improvement of functional properties.

Table 1.

Structural changes and functional properties of plant proteins interacting with phenolic acids.

Protein	Phenolic acid	Interaction	Structural	Functional	References
SPI	CGA	Non-covalent interaction	Charged amino acid residues, ζ potential ↑ α-helix ↓, β-sheet ↓, β-turns ↓	7.86 % higher solubility than without CGA; Inhibited E. coli and S. aureus DPPH Free radical scavenging rate 46.67 ± 0.58 %	(Zhu et al., 2024)
		Covalent interaction	Particle size ↓ ζ-potential ↑ α-helix↓, β-sheet↓, β-turn↑, random coil↑ Protein defolding	13.55 % higher solubility than without CGA; Enzymatic method DPPH Free radical scavenging rate 52.32 ± 0.49 % Alkaline DPPH Free radical scavenging rate 48.78 ± 1.36 %	(Shi et al., 2022)
	GA	Covalent interaction	α-helix ↓ Exposure of aromatic amino acid residues in protein structures	DPPH free radical scavenging capacity was approximately 74.19 ± 0.45 %, which was nearly 5-fold higher compared to unmodified SPI, respectively; Anti-free radicals	(Wang, You, et al., 2022a)
Zein	CGA	Non-covalent interaction (hydrogen bonding and electrostatic interactions)	Particle size ↓ Tyrosine residue concentration ↑ Tryptophan residue concentration ↓	Increased solubility	(Wang, Chen, et al., 2024)
	GA	Non-covalent interaction/ Covalent interaction	ζ-potential ↓ Loose spatial conformation	Non-covalent DPPH radical scavenging rate 72.57 ± 0.91 % Covalent interaction DPPH radical scavenging 80,63 ± 0.46 %	(Zhang, Wang, et al., 2025)
Cannabis sativa isolate protein	GA	Covalent interaction	Hydrophilic group↑ Particle size ↓	Improve the solubility and emulsifying properties of proteins	(Liu et al., 2023)
Pea protein	GA	Covalent interaction	Particle size, ζ-potential, Active site ↑	DPPH free radical scavenging increased by 7.2 %	(Zhang et al., 2023)

Alkali treatment is more suitable for the formation of protein-phenolic acid complexes because it is simple and stable compared to enzyme-catalyzed cross-linking, does not introduce new proteins, and is not limited by enzyme specificity and does not require complex modulation of enzyme activity (Pi et al., 2022). Xiaowen Pi et al. (Pi et al., 2023) studied the covalent coupling reaction of SPI with GA and caffeic acid (CA) under alkali treatment conditions with GA and caffeic acid (CA) under alkali treatment, in which the vibrational bands of amide A, amide I and amide II, which correspond to the N—H stretch, C—O stretch, and N—H bending and C—N stretch vibrations in proteins, can be observed. The positions of these vibrational bands were shifted, indicating that the phenolic acid covalently reacted with the C—O, N—H and C—N groups of SPI, and the phenolic acid was successfully attached to SPI and led to the change of the secondary structure of SPI. The molecular changes of peanut proteins after covalent binding to CGA and EGCG were shown by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).Both CA and EGCG covalently bound to peanut proteins in alkali treatment and covalent binding of phenolic acids such as CA was stronger than that of EGCG as derived from the grafting efficiencies of the two types of complexes (He et al., 2020).

Besides, enzymatic covalent cross-linking is a highly specific and green cross-linking method. In practical applications, laccase is usually used to catalyze the covalent binding of plant proteins with phenolic acids (Feng et al., 2023). The sulfhydryl groups, amino groups, and tyrosine residues on the side chains of the plant protein molecules are able to react with the phenolic acids oxidized by laccase in a linkage reaction, thus realizing the covalent cross-linking (Pham et al., 2019). Shi Jiahui et al. (Shi et al., 2022) investigated the enzymatic covalent modification of SPI by different concentrations of CGA in the covalent interaction of SPI with CGA. The researchers used SPI as a control to analyze the structural changes in the complexation of SPI with CGA. The spectra showed two characteristic absorption peaks at 280 nm and 325 nm and a shoulder peak at 322 nm for SPI and CGA complexes, respectively. This is due to the exposure of tryptophan and tyrosine residues at a wavelength of 280 nm, the formation of a complex between the two at 325 nm, and the oxidation of CGA to quinone catalyzed by laccase at 322 nm, respectively. Moreover, the homogeneous particle size of the enzymatically modified complexes in the covalent interaction resulted in improved foaming stability of the complex solution and increased protein solubility. Therefore, the stability of the complexes prepared by enzymatic method was higher than that of the complexes prepared by alkaline method.

Compared to reversible non-covalent interactions, irreversible covalent interactions not only exhibit greater strength and longer-lasting effects but also demonstrate superior thermal stability, antioxidant activity, and bioavailability (Zhou, Meng, et al., 2023). Jia et al. (Jia et al., 2022b) investigated the covalent and non-covalent modifications of CGA on sunflower seed protein. CGA was added to sunflower seed protein solutions at molar ratios ranging from 1:10 to 10:1 to facilitate interactions. Samples were induced to undergo non-covalent interactions at pH 7 and covalent interactions at pH 9 to evaluate the degree of protein modification, physicochemical properties, solubility, and gelation capacity. Results indicated that both non-covalent and covalent interactions positively influenced sunflower seed protein solubility. Samples with covalent modifications exhibited color changes at molar ratios of 1:1 or higher and achieved maximum gel strength.. Furthermore, in vitro digestion results of plant proteins interacting with phenolic acids suggested digestion efficiency may depend on whether they interact via covalent bonds. The study found that digestibility of covalent complexes increased with higher phenolic acid content. In contrast, covalent complexes proved more stable, better protecting phenolic acids from degradation (Chen et al., 2025). They remained in the gut longer, resisted digestion, and slowly released phenolic acids for sustained scavenging of reactive oxygen species (ROS) in neurons (Tian et al., 2022). This prevents ROS from damaging cell membranes, mitochondria, and synaptic structures, maintaining neuronal morphology and synaptic stability. It ensures normal inter-neuronal communication, reducing impairment of cognitive and memory functions (Lee et al., 2025). Wenyi Shi et al. (Shi et al., 2024) demonstrated that rice protein-FA covalent complexes exhibit higher digestive stability and better protection of phenolic acids than their non-covalent counterparts. Dai Shicheng et al. (Dai et al., 2023) concluded that covalent binding of SPI to catechin enhances catechin bioavailability and exhibits superior digestive resistance compared to non-covalent complexes. This stems from the more intact structure of the 7S and 11S subunits in their digestive products. Furthermore, covalent complexes induce more pronounced protein structural rearrangements than non-covalent interactions, thereby exerting greater influence on altered protein function.

4. Effect of phytoalexin-phenolic acid on neuronal secretion

After optimizing the interaction types, structural changes, and functions of plant proteins and phenolic acids, the focus of research has been on the mechanisms by which the complexes formed by the two affect neuronal secretion and thereby maintain nervous system function. Neurons, as the basic functional units of the nervous system, release neurotransmitters (e.g., dopamine, 5-hydroxytryptamine, glutamate, etc.) (Fujise et al., 2025), neurotrophic factors (e.g., brain-derived neurotrophic factor BDNF) (Ayankojo et al., 2025), and neuropeptides (e.g., endorphins) (Ghilardi et al., 2024)through synaptic vesicles to modulate emotional, cognitive, and motor functions(Ugrumov, 2024), to promote neuronal survival, and to regulate pain, sleep deprivation, and the stress response, which play an important role in maintaining the normal nervous system function and modulating neurodegenerative diseases (NDDs). In recent years, lactoferrin has been studied in combination with various polyphenols, for example, lactoferrin-curcumin rice particles were manufactured, which traveled from the nasal cavity to the brain via targeted delivery, and the complex was shown to be neuroprotective (Y. Li et al., 2024). Plant proteins and phenolic acids have all shown advantages in promoting neuronal secretion and in NDD. Plant proteins can be enzymatically hydrolyzed to produce biologically active peptides, for example, exopeptidases hydrolyze proteins by cleaving terminal peptide bonds to release amino acids, while endopeptidases hydrolyze proteins by disrupting the peptide bonds of non-terminal amino acids within the protein molecule, which in turn produces low molecular weight peptides with strong antioxidant properties (Fadimu et al., 2022). Hydrophobic amino acids such as tryptophan, phenylalanine, leucine, isoleucine, threonine, and valine are also exposed during the hydrolysis process, providing essential precursors for neurotransmitter synthesis, and Martin Reuter et al. (Reuter et al., 2021) reported that tryptophan (TRP), one of the essential amino acids, has been identified as a substance with a potentially protective effect on physical and mental health. TRP is recognized as a potentially protective substance for physical and mental health, as it not only positively influences many physiological processes in the human body through the use of gut microbiota, but also acts as a precursor to the neurotransmitter 5-HT, which is known to regulate mood, appetite, and sleep, as well as alleviate depressive symptoms (Polyiam & Thukhammee, 2024a). In addition to this, plant proteins reduce neurotransmitter degradation by inhibiting monoamine oxidase (MAO) activity. Phenolic acids play a strong antioxidant role due to their unique catechol structure, which can scavenge free radicals, protect neurons from oxidative damage, and activate the Nrf2 and NF-κB pathways, modulating the crosstalk between signaling pathways to inhibit hippocampal neuronal apoptosis (Zhang et al., 2024). CGA, as a hydroxycinnamic acid derivative, has a catechol structure and an acrylic side chain, and it is endowed with free radical scavenging and metal chelating abilities. It exerts neuroprotective effects by regulating oxidative stress and neuroinflammatory pathways, which can improve anxiety-like behaviors and increase the survival rate of dopaminergic neurons .Can Tang et al. (Tang et al., 2025) observed that dendritic complexity was reduced in the hippocampal DG region of rats treated with a single prolonged stress treatment, and dendritic length, branching number and dendritic spine density were decreased. In contrast, CGA (30 mg/kg and 60 mg/kg) treatments significantly increased dendritic complexity, length, number of branches, and dendritic spine density, suggesting that CGA promotes structural plasticity of hippocampal synapses. Plant proteins and phenolic acids, through non-covalent or covalent interactions, would produce synergistic effects to enhance bioactivity, stability and antioxidant activity. The mechanisms of plant protein-phenolic acid interactions on neuronal secretion will be presented in terms of anti-oxidative stress and neuroprotection, protection and controlled release of precursor amino acids, and gut-brain axis, respectively.

4.1. Anti-oxidative stress and neuroprotection

ROS act as signaling molecules actively involved in cellular homeostasis (Kračun et al., 2025), however, when ROS are generated in excess and cleared in insufficient quantities, the intracellular redox homeostasis is disrupted, placing the cell in a state of oxidative stress. The brain is the core region of oxygen metabolism in the body and is particularly vulnerable to oxidative stress (Shi et al., 2020). Overproduction of ROS in the brain leads to neuronal apoptosis, which in turn affects the balance of the neurotransmitter system, such as decreased levels of neurotransmitters such as 5-HT and dopamine. Usually with age, nigrostriatal dopaminergic neurons in the brain gradually decrease, and when the decrease reaches a certain level, it is prone to Parkinsonian-type disease with depression, anxiety, cognitive impairment and other psychiatric symptoms. As a class of natural antioxidants, phenolic acids possess outstanding free radical scavenging capabilities and help regulate the body's oxidative stress balance (Li, He, et al., 2021). It has been found that CGA can inhibit the overproduction of reactive oxygen species, keep reactive oxygen species in a controlled state, reduce the damage to brain cells caused by oxidative stress, and maintain the integrity of brain cells, as well as inhibit the expression of genes encoding antioxidant-related proteins. Protocatechuic acid (PCA) is a dihydroxybenzoic acid, which is mainly found in green tea and fruits. Song Lee et al. (Lee et al., 2018) performed Fluoro-Jade-B (FJB) staining and 4-Hydroxynonenal (4HNE) staining to demonstrate whether PCA improves neuronal survival and reduces oxidative damage in the hippocampus, and for the detection of neuronal death and oxidative stress after seizures. The results showed that treatment with PCA after seizures reduced ROS production and had a positive effect on oxidative damage, microglia activation and neurodegeneration. Thus, PCA treatment has high therapeutic potential for seizure-induced neuronal death. However, phenolic acids are prone to oxidation. Compared to individual components, the presence of electron transfer processes between plant protein-phenolic acid complexes causes changes in protein conformation, resulting in the complex exhibiting significantly greater antioxidant capacity than its individual components (de Morais et al., 2020). When plant proteins interact with phenolic acids such as CGA and protocatechuic acid, sulfur-containing amino acids (e.g., cysteine, methionine) in plant proteins provide the -SH moiety to regenerate glutathione (GSH).GSH is a tripeptide consisting of glutamic acid, cysteine, and glycine. It is known as a major cellular antioxidant involved in the maintenance of intracellular redox state and plays an important role in scavenging superoxide and ROS in the brain (Gao, Zhang, et al., 2025).Studies have shown that GSH is important for normal brain function and protects against neuronal toxicity injury. A deficiency of GSH in the brain predisposes to Parkinson's disease, Alzheimer's disease, seizures and other NDDs (Kubát et al., 2024). In addition to this, PCA also preserves the level of neuronal GSH.

The signaling pathway of Nrf2 is associated with cytoprotection by controlling detoxification enzymes, anti-apoptotic proteins, and proteasomes, which are important regulators of antioxidants in the cellular defense system (Wen et al., 2019). As shown in Fig. 3,the activation of Nrf2 as a key transcription factor by the phycobiliprotein-phenolic acid complex regulates the expression of a series of antioxidant enzymes and further enhances the antioxidant defenses of cells (Gao, Wang, et al., 2025). Plant proteins such as SPI, which has some antioxidant capacity itself, can regulate the Nrf2-Ho1 signaling pathway and inhibit oxidative stress by adjusting the expression of antioxidant enzymes. Zhao et al. (Zhao et al., 2021) measured the superoxide anion scavenging activity, iron reduction capacity, and the role of SPI in regulating Nrf2-regulated antioxidant enzymes in human intestinal Caco-2 cells in a study on the antioxidant potential of selenium-enriched SPI in regulating the Nrf2-Ho1 signaling pathway The results showed that Se-rich SPI reduced oxidation by activating the Nrf2 pathway, leading to increased levels of SOD and GPX, two antioxidant enzymes that are key influences in reducing oxidative stress.CGA also scavenges ROS and activates the Nrf2 signaling pathway, inhibiting mRNA expression of key molecules in the NF-κB and NLRP3 signaling pathways and protein abundance (Huang et al., 2025). Plant proteins can synergize with phenolic acids to activate the endogenous antioxidant system and inhibit the oxidative stress signaling pathway, which together protect against oxidation.

Fig. 3.

Diagram of Nrf2 signaling pathway and mechanism of tryptophan metabolis influenced by plant protein-phenolic acid.

4.2. Gut-brain axis mechanisms

Free phenolic acids exhibit relatively limited solubility in aqueous systems and are readily degraded by gastric acid and hydrolyzed by intestinal enzymes. Only a small fraction of intact phenolic acids reaches the colon to participate in gut-brain axis-related regulation (Truzzi et al., 2021). The low intestinal permeability of phenolic acids results in poor oral bioavailability, significantly limiting their potential applications in the nervous system. Plant protein peptides can enhance the solubility and dispersion of phenolic acids in water. Conversely, phenolic acids stabilize plant protein peptides, preventing denaturation under heated conditions while reducing protease-mediated hydrolysis damage (Yan et al., 2025). The structures formed by non-covalent or covalent bonds between plant proteins and phenolic acids enhance the stability of phenolic acids in the gastrointestinal tract. These complexes can reach the large intestine intact, where the large intestine—as the primary habitat for gut microbiota—enables targeted and sustained effects on microorganisms (Zhou, Meng, et al., 2023). To address this issue, Miao Ruimin et al. (Miao et al., 2022) investigated a novel upper intestinal absorbable polymer-lipid hybrid nanoparticles (PLN). PLN employ a lipid core to encapsulate phenolic acids and decanoic acid-modified canola proteins as the biopolymer shell, aiming to improve the stability, retention, and permeation ability of phenolic acids in the gastrointestinal tract. The vegetable protein shell protects phenolic acids in the stomach and small intestine from damage by gastric acid, digestive enzymes, etc., allowing them to reach the colon. The hydroxyl and carboxyl groups of phenolic acids can form hydrogen bonds with the hydroxyl groups of cellulose or hemicellulose in the cell wall, interfering with their crystalline structure and causing damage to the cell wall, leading to an increase in the permeability of the cell membrane, generating antimicrobial properties, and improving the intestinal micro-ecological balance (Tang et al., 2022). Eva Moll et al. (Moll et al., 2023) incorporated ferulic and coumaric acids separately into polyhydroxybutyrate-hydroxyvalerate films and analyzed the antimicrobial effects of these films against Escherichia coli and Listeria monocytogenes, as well as the release kinetics of phenolic acids. The results showed that the phenolic acid-loaded films were able to inhibit the growth of bacteria close to 2 log CFU. Gut microorganisms (Oh & Yoon, 2024) hydrolyze plant proteins into amino acids and peptides by extracellular proteases and peptidases, which can be further metabolized and utilized by the microorganisms to produce a wide range of metabolites, such as short-chain fatty acids (SCFAs, e.g., acetic acid, propionic acid, butyric acid). Among them, SCFAs are a class of fatty acids composed of carbon chains with a length of 1–6 carbon atoms, which are produced indirectly through microbial metabolism, and can promote the growth and repair of intestinal epithelial cells, enhance the intestinal barrier function, reduce the entry of harmful substances into the bloodstream such as lipopolysaccharides, and provide a stable environment for the survival of the intestinal flora, so that the beneficial bacteria can perform their metabolic functions normally. As shown in Fig. 2, there is a two-way communication system between the gut and the brain (Needham et al., 2020). Gut neurons communicate with the central nervous system through neuronal (vagal), endocrine, and immune pathways, and the mechanism of the whole process is called the microbiota-gut-brain axis (Zeng et al., 2023). SCFAs acts on FFAR 2 and FFAR 23, affecting the secretion of intestinal hormones, such as GLP-1, which has neuroprotective effects (Tan et al., 2023). It modulates the inflammatory state of microglia and inhibits pro-inflammatory signaling pathways through NF-κB inhibition and Erk1/2 activation, thereby reducing the risk of depression. Researchers have shown that metabolic byproducts produced by the gut microbiota, such as short-chain fatty acids, lipopolysaccharides, and bile acids, as well as neurotransmitters and inflammatory mediators within the gut-brain axis, can modulate neurons. It is through gut-brain axis interactions that obesity and depression disrupt gut microbiota homeostasis. Animal studies have also shown that microbial colonization affects development and stress response in calves (Du et al., 2023). In contrast, antioxidant supplementation may modulate the gut-brain axis, providing a new therapeutic approach to obesity and depression. Future studies should go deeper in designing clinical trials to validate gut-brain axis-based mechanisms, which could facilitate integration between disciplines and provide new perspectives for the prevention and treatment of mood disorders.

Fig. 2.

Comparison diagram of the effects of plant protein-phenolic complexes and free phenolic acids on the gut-brain axis mechanism.

4.3. Metabolism of precursor amino acids

Interaction of plant proteins with phenolic acids causes the proteins to be defolded and their hidden hydrophobic groups of amino acid residues to be exposed to the hydrophilic exterior of the plant protein (Geng et al., 2022). For example, the interaction of wheat alcohol soluble proteins with CGA can change the protein conformation, exposing the aromatic heterocyclic hydrophobic moieties of tryptophan and tyrosine residues in the protein molecule (Wang, Li, et al., 2022). After the plant protein–phenolic acid complex optimizes the gut microenvironment and establishes the basis for ‘gut–brain’ communication through the gut–brain axis mechanism, the complex can further support neurotransmitter synthesis in neurons by regulating the release and metabolism of precursor amino acids (Xia et al., 2025).

Tryptophan (TRP) is an essential amino acid in the human body and is involved in various physiological processes, such as the maintenance of neuronal function, regulation of immunity and the safeguarding of intestinal homeostasis. Since the human body is unable to synthesize TRP, TRP cannot be synthesized through the body's own metabolism and must be obtained from food, and plant proteins are a good source of TRP (Torres et al., 2023). In the human body TRP involves three main metabolic pathways: the kynurenine metabolic pathway, the 5-HT metabolic pathway, and the indole derivative metabolic pathway. Most TRPs are metabolized to produce kynurenine, and the remaining TRPs are oxidized, decarboxylated to form 5-HT or metabolized by microorganisms to form indole derivatives. Tryptophan is converted to N -formylkynurenine by tryptophan 2,3-dioxygenase (TDO) or indole 2,3-dioxygenase (IDO), which later generates kynurenine by the action of formylase (Mouttoulingam & Taleb, 2024). Kynurenine can be catalyzed by kynurenine hydroxylase to generate 3-hydroxykynurenine, which is further metabolized to form quinolinic acid (QUIN). QUIN is a competitive agonist of the N-methyl-d-aspartate (NMDA) receptor in the central nervous system, and if the receptor is over-activated, ROS will be generated, causing damage to the organism and affecting neuronal function. In addition, kynurenine can generate kynurenine quinolinic acid under the action of kynurenine aminotransferase. Kynurenine quinolinic acid is an endogenous neuroactive substance that regulates excitatory transmission in the central nervous system and reduces neuronal cell loss due to excessive release of excitatory amino acids, thereby reducing extracellular glutamate and dopamine levels. Part of TRP generates 5-hydroxytryptophan under the action of tryptophan hydroxylase, and then is decarboxylated catalytically by 5-hydroxytryptophan decarboxylase. 5-HT, as a neurotransmitter, is involved in the regulation of physiological processes, such as mood, sleep, and appetite. Studies have found that abnormal levels of 5-HT are often associated with mental illnesses such as depression. The researchers tested 5-HT levels in mice with the help of a fluorescent sensor that expresses 5-HT in cerebellar lobule VII. At the same time, fiber-optic photometry was used to measure the fluorescence changes of the sensor during anxiety behavior in the elevated zero maze. The results showed that the 5-HT level in leaflet VII increased when the anxiety level of male mice was low, and decreased when the anxiety level of mice was high. In the presence of gut microbes, TRP is metabolized to indole derivatives, such as indole and indole propionic acid. Gut health is closely related to brain function, and indole can be involved in regulating intestinal immunity, activating immune cells in the gut and enhancing intestinal immune function.

The tyrosine (TYR) metabolic pathway plays a key role in brain function, and TYR in the metabolic pathway synthesizes dopamine and norepinephrine in the presence of tyrosine hydroxylase. Dopamine and norepinephrine are important neurotransmitters that regulate cognitive functions, emotions and stress responses. Fang et al. (Fang et al., 2025) summarized that L-tyrosine can alleviate the neuronal reduction caused by valproic acid action in the DG and CA1 hippocampal regions of mice. In experiments using autistic mice as a model, the hippocampus of mice treated with L-tyrosine showed altered gene expression profiles as well as different neurotransmitter levels, along with attenuated colonic barrier damage and improved composition and function of gut microbes. Patricia Hernandez et al. (Hernandez et al., 2025) showed the enrichment of identified metabolites in all the identified metabolic pathways and found that the two most relevant pathways affecting neurotransmitters are TRP and TYR biosynthesis. As precursors of the neurotransmitters 5-HT and catecholamines (dopamine, norepinephrine, and epinephrine), these aromatic amino acid metabolisms have important functions in brain physiology.

5. Conclusion and prospect

In this study, the effects of novel food-grade plant proteins and phenolic acids on neuronal secretion were investigated in depth, and it was found that both of them showed positive effects on the maintenance of normal physiological functions of neurons and the prevention of related diseases. Vegetable proteins provide key amino acids for neurons to ensure their structural stability and normal function, and also play an important role in regulating the synthesis and release of neurotransmitters, which helps to maintain the signaling of the nervous system. Phenolic acid reduces oxidative damage to neurons by virtue of its significant anti-oxidative stress capacity, thereby reducing the risk of NDDs. In terms of inflammation regulation, phenolic acid inhibits neuroinflammatory responses and protects neurons from inflammatory damage. In addition, both of them have indirect effects on neuronal secretion by regulating the gut-brain axis mechanism and tryptophan metabolism, highlighting the close association between the gut microbiota and the nervous system. In the future, in the investigation of mechanisms of action, it will be necessary to further clarify the specific molecular targets and signaling pathways through which plant protein–phenolic compound complexes regulate neuronal secretion. Beyond oxidative stress, other signaling pathways such as apoptosis regulation and neurotransmitter receptor activation should be explored to uncover more potential mechanisms of action. In studies of combined applications, considering the differences in characteristics of plant proteins and phenolic compounds from different sources, comparative experiments are needed to screen raw materials with better neuroprotective effects. Research should delve deeper into the optimal combination methods and dosage ratios of plant protein–phenolic compound complexes, clarifying dose–response relationships and evaluating their synergistic effects. For instance, low doses of phenolic compounds may enhance neuroprotective effects, whereas high doses may induce cellular damage due to oxidative properties or interfere with amino acid absorption by excessive binding to proteins. Additionally, because the human nervous system is more complex, its function is significantly influenced by individual differences such as age, sex, underlying diseases, and gut microbiota composition, which are difficult to fully simulate in simple model organisms. Verifying the safety and efficacy of plant protein–phenolic compound complexes in humans and promoting their translation from basic research to practical applications is of significant practical importance for improving human neurological health.

CRediT authorship contribution statement

Xiaoyu Zhang: Writing – review & editing, Writing – original draft, Visualization, Investigation, Conceptualization. Yutong Zheng: Writing – original draft, Visualization. Xinyu Wang: Writing – original draft, Visualization. Jiannan Yan: Writing – review & editing. Jingsheng Liu: Writing – review & editing. Hao Zhang: Writing – review & editing, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.