Food-Derived Bioactive Peptides: From Generation and Identification to Therapeutic and Functional

2.1 Animal-Derived Sources

2.2 Plant-Derived Sources

Plant proteins have emerged as important and sustainable sources of bioactive peptides due to their availability, lower environmental impact, and increasing consumer preference for plant-based nutrition. Although plant proteins may differ from animal proteins in amino acid composition and digestibility, many plant-derived peptides exhibit significant biological activities [18].

2.3 Emerging and Alternative Sources of Bioactive Peptides

The increasing demand for sustainable protein production has encouraged researchers to explore unconventional sources of bioactive peptides. Algae, microorganisms, and insect proteins represent emerging resources with considerable potential [17].

3.1 Enzymatic Hydrolysis

performance.

Limitations Typical Food Representative Sources Bioactivities Complex downstream E. coli, yeast, Therapeutic peptides, processing; expensive insect cells, AMPs, anticancer production plant systems peptides Requires advanced Engineered Improved production biotechnology, high proteases of high-value development cost bioactive peptides Requires experimental In silico Rational design of validation, depends on peptide antioxidant, ACE database quality libraries inhibitory, antimicrobial and anti-inflammatory peptides

Enzymatic hydrolysis is the most extensively applied method for producing food-derived bioactive peptides because it provides high substrate specificity while preserving the nutritional quality of proteins. During hydrolysis, proteolytic enzymes cleave peptide bonds at specific amino acid residues, releasing peptides with defined molecular weights and biological activities. Compared with chemical hydrolysis, enzymatic hydrolysis operates under relatively mild conditions, minimizing amino acid degradation, undesirable side reactions, and the formation of toxic by-products. Consequently, this approach has become the preferred strategy for producing bioactive peptides intended for food, pharmaceutical, and nutraceutical applications. The selection of proteolytic enzymes is one of the most critical factors influencing peptide production. Both animal-derived digestive enzymes and microbial proteases are commonly employed depending on the desired peptide profile. Among commercial enzymes, Alcalase has been widely used because of its broad substrate specificity and high hydrolytic efficiency. Trypsin preferentially cleaves peptide bonds adjacent to lysine and arginine residues, whereas pepsin primarily hydrolyzes peptide bonds associated with aromatic amino acids under acidic conditions. Papain, Bromelain, Flavourzyme, Neutrase, and Protamex have also been extensively utilized either individually or in combination to improve peptide diversity and biological activity [15].

The physicochemical properties of the hydrolysis process substantially influence both peptide composition and functionality. Factors including enzyme-to-substrate ratio, temperature, pH, hydrolysis time, substrate concentration, and degree of hydrolysis collectively determine peptide yield, molecular weight distribution, and biological efficacy. Excessive hydrolysis may generate very small peptides or free amino acids, which can reduce certain biological activities, whereas insufficient hydrolysis may fail to release the desired bioactive sequences. Therefore, optimization of hydrolysis conditions is essential for maximizing functional

Enzymatic hydrolysis has been successfully applied to numerous food proteins, including milk caseins, whey proteins, fish collagen, soybean proteins, pea proteins, cereal proteins, and egg proteins. Depending on the parent protein and enzyme combination, hydrolysates may exhibit antioxidant, antihypertensive, antimicrobial, anti-inflammatory, antidiabetic, or immunomodulatory properties. Advances in response surface methodology, AI-assisted optimization, and computational enzyme selection have further improved the efficiency of enzymatic peptide production while reducing production costs. Despite its numerous advantages, enzymatic hydrolysis also presents several challenges. Commercial enzymes can be expensive, enzyme recovery is often difficult, and large-scale industrial processes require careful optimization to ensure reproducibility and economic feasibility. Moreover, controlling peptide bitterness, which frequently results from extensive protein hydrolysis, remains an important challenge for the incorporation of peptide hydrolysates into functional foods. The characteristics of proteolytic enzymes largely determine peptide yield, molecular weight distribution, and biological activity [23]. The major commercial proteases commonly used for bioactive peptide production are summarized in Table 4.

3.2 Microbial Fermentation

Microbial fermentation represents another important strategy for producing bioactive peptides and has been widely employed in the manufacture of fermented dairy products, meat products, soy-based foods, and cereal-derived foods. During fermentation, microorganisms synthesize extracellular and intracellular proteases capable of hydrolyzing food proteins and releasing biologically active peptide sequences. Unlike direct enzymatic hydrolysis, fermentation simultaneously enhances food preservation, improves sensory characteristics, and increases nutritional value. LAB, including species of Lactobacillus, Lactococcus, Streptococcus, and Bifidobacterium, are the most extensively studied microorganisms for peptide production. Their highly efficient proteolytic systems enable the degradation of complex proteins into short peptides with various physiological functions. Numerous studies have reported ACE inhibitory, antioxidant, antimicrobial, immunomodulatory, and anti-inflammatory peptides generated during the fermentation of milk, soy, cereals, and legumes. Compared with enzymatic hydrolysis, microbial fermentation is generally considered a more natural process and is highly compatible with clean-label food production. Nevertheless, peptide production depends strongly on microbial strain selection, fermentation conditions, substrate composition, and incubation time, making process optimization essential for obtaining reproducible results [24].

3.3 Emerging Production Technologies

Rapid advances in biotechnology have introduced innovative approaches for producing bioactive peptides beyond conventional hydrolysis and fermentation. Precision fermentation, synthetic biology, recombinant DNA technology, and enzyme engineering have enabled the controlled production of specific peptide sequences with improved efficiency and consistency. Precision fermentation utilizes genetically optimized microorganisms capable of producing target proteins or peptide precursors under highly controlled conditions. Recombinant expression systems have also been investigated to generate peptide-rich proteins that can subsequently undergo enzymatic processing. Meanwhile, enzyme engineering has improved the catalytic performance, stability, and substrate specificity of proteolytic enzymes, thereby enhancing peptide yield and reducing processing time. In parallel, bioinformatics, molecular docking, and AI have become valuable tools for predicting bioactive peptide sequences before experimental validation. These computational approaches significantly reduce screening time, facilitate enzyme selection, and accelerate the discovery of novel peptides with desired biological properties. As computational biology continues to evolve, AI-assisted peptide design is expected to play an increasingly important role in the development of next-generation functional ingredients [20].

3.4 Factors Influencing Peptide Production

Regardless of the production method employed, the quantity and biological activity of released peptides are strongly affected by multiple processing parameters. The intrinsic characteristics of the parent protein, including amino acid composition, tertiary structure, and accessibility of peptide bonds, largely determine the potential for generating bioactive sequences. Likewise, processing conditions directly influence peptide size, stability, and functionality. Among the operational variables, pH and temperature are particularly important because they regulate enzyme activity and protein denaturation. Hydrolysis duration and enzyme concentration determine the degree of hydrolysis and consequently the molecular weight distribution of the resulting peptides. In addition, pretreatment methods such as ultrasound, high-pressure processing, microwave-assisted processing, and pulsed electric fields have recently been explored to improve protein accessibility and enhance enzymatic efficiency. No single production strategy is universally applicable to all protein sources. Instead, the selection of an appropriate method should consider the characteristics of the raw material, the targeted biological activity, production cost, scalability, and intended industrial application. Continuous integration of conventional processing technologies with modern biotechnological and computational approaches is expected to further improve the sustainable production of food-derived bioactive peptides and facilitate their commercialization in functional foods, nutraceuticals, and pharmaceutical products [25].

The overall workflow for the production and characterization of food-derived bioactive peptides involves a series of interconnected steps, including protein source selection, pretreatment, peptide generation, purification, analytical identification, biological evaluation, and subsequent industrial utilization. A schematic overview of this integrated process is presented in Fig 1.

4.1 Peptide Separation and Purification

The initial hydrolysates obtained from protein sources generally contain highly complex mixtures of peptides with different molecular weights, charges, hydrophobicities, and biological activities. Consequently, purification is an essential step to isolate peptide fractions with specific functional properties before structural characterization and biological evaluation. Membrane-based separation technologies, particularly ultrafiltration, are widely employed as preliminary purification methods because they efficiently fractionate peptides according to molecular weight while maintaining biological activity. Membrane filtration also offers advantages such as simplicity, scalability, low chemical consumption, and compatibility with industrial production. Chromatographic techniques are subsequently applied to achieve higher purification efficiency. Size-exclusion chromatography separates peptides based on molecular size, whereas ion-exchange chromatography utilizes differences in peptide charge. Reverse-Phase High-Performance Liquid Chromatography (RP-HPLC) remains the most frequently used purification technique owing to its excellent separation efficiency, reproducibility, and compatibility with downstream mass spectrometric analysis. In many studies, combinations of ultrafiltration and RP-HPLC are employed to obtain highly purified peptide fractions for structural identification [25].

4.2 Structural Identification of Bioactive Peptides

Following purification, peptide sequences must be accurately identified to establish structure–activity relationships. Among the available analytical techniques, mass spectrometry has become the cornerstone of peptide identification due to its exceptional sensitivity, specificity, and ability to analyze complex peptide mixtures. LC-MS/MS is currently regarded as the gold standard for peptide sequencing. The combination of chromatographic separation with high-resolution mass spectrometry enables precise determination of peptide molecular weights and amino acid sequences, even in highly complex food matrices. MALDI-TOF MS is another widely used technique that provides rapid molecular mass determination and peptide fingerprinting with minimal sample preparation. In addition to mass spectrometry, amino acid composition analysis, Edman degradation, and NMR spectroscopy may be employed for detailed structural characterization of selected peptides. Although these techniques are generally less suitable for high-throughput analysis, they provide valuable information regarding peptide conformation, structural stability, and molecular interactions [26].

4.3 Bioinformatics and in Silico Approaches

The rapid development of bioinformatics has transformed the discovery of food-derived bioactive peptides. Instead of relying solely on experimental screening, researchers increasingly utilize computational approaches to predict peptide sequences with desired biological activities before laboratory validation. Several specialized databases containing experimentally validated bioactive peptides facilitate sequence comparison and functional prediction. Machine Learning (ML) algorithms and Quantitative Structure-Activity Relationship (QSAR) models are increasingly employed to identify peptide characteristics associated with antioxidant, antihypertensive, antimicrobial, anti-inflammatory, and antidiabetic activities. Molecular docking simulations further enable researchers to investigate interactions between peptides and biological targets, including ACE, Dipeptidyl Peptidase-IV (DPP-IV), cyclooxygenase enzymes, and inflammatory mediators. AI has recently emerged as a powerful tool for peptide discovery by integrating protein sequence information, enzymatic cleavage prediction, structural modeling, and biological activity prediction. These computational strategies substantially reduce experimental workload, shorten development time, and improve the efficiency of identifying promising peptide candidates [27].

4.4 Structure-Activity Relationships

The biological functions of food-derived peptides are closely associated with their structural characteristics. Peptide length, molecular weight, amino acid composition, sequence arrangement, hydrophobicity, net charge, and three-dimensional conformation collectively determine biological activity. Short peptides consisting of two to twenty amino acid residues generally exhibit superior gastrointestinal absorption and higher bioavailability than larger peptides. Hydrophobic amino acids such as leucine, isoleucine, valine, phenylalanine, and tryptophan often contribute to antioxidant and antimicrobial activities by facilitating interactions with lipid membranes and free radicals. Positively charged amino acids, including lysine and arginine, are commonly associated with antimicrobial activity because they promote electrostatic interactions with negatively charged bacterial membranes. Similarly, the presence of proline residues at the C-terminal region frequently enhances ACE inhibitory activity, while aromatic amino acids contribute to radical scavenging capacity through hydrogen donation and electron transfer mechanisms. Understanding these structure-activity relationships is fundamental for the rational design of functional peptides with enhanced efficacy and improved stability. The integration of advanced purification techniques, high-resolution analytical platforms, and computational prediction tools has substantially accelerated the identification of food-derived bioactive peptides. These multidisciplinary approaches provide the scientific foundation for elucidating peptide mechanisms of action and facilitate the development of novel functional ingredients for food, nutraceutical, and pharmaceutical applications. A variety of analytical techniques have been developed for the separation, purification, identification, and structural characterization of food-derived bioactive peptides [25]. The principles, applications, advantages, and limitations of the major analytical methods are summarized in

5.1 Antioxidant Activity

metal chelation [29].

Main application Principle Technique Initial fractionation Separation based on Ultrafiltration molecular weight Peptide purification Separation according to Size-exclusion molecular size chromatography (SEC) Peptide purification Separation based on charge Ion-exchange chromatography (IEC) Final purification Separation based on RP-HPLC hydrophobicity Peptide identification Mass analysis and peptide LC–MS/MS sequencing Molecular weight Laser desorption ionization MALDI-TOF MS determination Sequence Sequential amino acid Edman degradation confirmation identification Three-dimensional Structural characterization NMR spectroscopy structure Mechanism prediction Computational interaction Molecular docking analysis

5.2 Antihypertensive Activity

Hypertension remains one of the leading risk factors for cardiovascular diseases and premature mortality worldwide. Persistent elevation of blood pressure significantly increases the incidence of stroke, heart failure, myocardial infarction, and chronic kidney disease. Although pharmacological antihypertensive agents effectively reduce blood pressure, long-term medication may cause adverse effects, prompting increasing interest in naturally occurring compounds capable of supporting cardiovascular health. Among food-derived bioactive peptides, antihypertensive peptides have received particular attention because of their ability to inhibit ACE, a key component of the renin–angiotensin system. ACE catalyzes the conversion of angiotensin I into the potent vasoconstrictor angiotensin II while simultaneously degrading bradykinin, an endogenous vasodilator. Inhibition of ACE therefore reduces angiotensin II formation, promotes vasodilation, decreases vascular resistance, and ultimately lowers blood pressure. The ACE inhibitory activity of peptides depends strongly on their structural characteristics.

Short peptides composed of two to twelve amino acid residues generally exhibit the highest inhibitory potency [30]. The presence of hydrophobic or aromatic amino acids, particularly proline, phenylalanine, tyrosine, tryptophan, leucine, and valine at the C-terminal region, has been associated with enhanced binding affinity toward the active site of ACE. Molecular docking studies have further demonstrated that hydrogen bonding, hydrophobic interactions, and electrostatic forces collectively determine peptide enzyme interactions and inhibitory efficiency. Milk proteins remain the most extensively investigated sources of antihypertensive peptides, with numerous ACE inhibitory sequences identified from casein and whey proteins. In addition, bioactive peptides exhibiting antihypertensive activity have been isolated from fish proteins, marine collagen, soybean, pea, rice bran, egg proteins, meat proteins, and fermented foods. Fermentation with lactic acid bacteria has proven particularly effective in generating potent ACE inhibitory peptides through microbial proteolysis. Besides ACE inhibition, several food-derived peptides regulate blood pressure through complementary mechanisms. Some peptides enhance endothelial nitric oxide production, thereby improving vascular relaxation and endothelial function. Others exhibit antioxidant and anti-inflammatory activities that indirectly contribute to cardiovascular protection by reducing vascular oxidative stress and chronic inflammation. These multifunctional mechanisms suggest that antihypertensive peptides may provide broader cardiovascular benefits than conventional single-target therapies. Although numerous in vitro and animal studies have confirmed the antihypertensive potential of food-derived peptides, clinical translation remains challenging. Factors including gastrointestinal stability, intestinal absorption, metabolic degradation, dosage optimization, and interindividual variability influence the effectiveness of orally administered peptides. Consequently, future research should emphasize human clinical trials, advanced delivery systems, and peptide formulation strategies to improve bioavailability and maximize therapeutic efficacy [31].

5.3 Antimicrobial Activity

The rapid emergence of antimicrobial resistance has become one of the most pressing global public health challenges, necessitating the development of novel antimicrobial agents with improved efficacy and lower potential for resistance development. In this context, food-derived bioactive peptides have attracted increasing attention as natural antimicrobial compounds due to their broad-spectrum activity against bacteria, fungi, and certain viruses. Unlike conventional antibiotics that often target specific metabolic pathways, many AMPs exert their effects through multiple mechanisms, thereby reducing the likelihood of microbial resistance. The antimicrobial activity of bioactive peptides is closely associated with their physicochemical properties, including peptide length, net positive charge, hydrophobicity, amphipathicity, and amino acid composition. Most AMPs are relatively short, containing between 10 and 50 amino acid residues, and possess positively charged amino acids such as lysine and arginine. These cationic residues facilitate electrostatic interactions with negatively charged microbial membranes, while hydrophobic amino acids promote membrane insertion and disruption [32]. The primary mechanism of AMPs involves destabilization of microbial cell membranes. Following electrostatic attraction to the cell surface, peptides penetrate the lipid bilayer and induce membrane permeabilization through several proposed models, including the barrel-stave, toroidal pore, and carpet mechanisms. Membrane disruption ultimately results in leakage of intracellular components, loss of membrane integrity, dissipation of ion gradients, and cell death. In addition to membrane-targeting effects, several peptides interfere with intracellular processes by inhibiting DNA and RNA synthesis, protein biosynthesis, enzyme activity, and essential metabolic pathways. Food-derived AMPs have been isolated from numerous protein sources. Milk proteins produce several well-characterized AMPs, including lactoferricin and lactoferrampin, which exhibit potent activity against both Gram-positive and Gram-negative bacteria. Egg-derived peptides such as lysozyme fragments possess bacteriolytic properties through degradation of bacterial cell walls. Fish proteins and marine collagen hydrolysates have also yielded AMPs capable of inhibiting foodborne pathogens and spoilage microorganisms. Furthermore, peptides derived from soybean, wheat, pea, and other plant proteins have demonstrated inhibitory effects against a variety of bacterial and fungal species, highlighting their potential as natural food preservatives [33]. Recent investigations have demonstrated that AMPs may also inhibit biofilm formation, an important virulence factor that contributes to persistent infections and antibiotic resistance. By preventing bacterial adhesion or disrupting mature biofilms, these peptides enhance microbial susceptibility to host immune responses and conventional antimicrobial agents. Such multifunctional properties have increased interest in their incorporation into active food packaging systems, edible coatings, and functional food formulations aimed at improving food safety and shelf life. Despite their considerable potential, several limitations remain regarding the commercial application of AMPs. Factors including susceptibility to enzymatic degradation, reduced activity under complex food matrices, potential cytotoxicity at high concentrations, and production costs continue to restrict large-scale implementation. Consequently, current research focuses on peptide modification, nanoencapsulation, and advanced delivery systems to improve peptide stability, bioavailability, and antimicrobial efficacy [34].

5.4 Anti-Inflammatory and Immunomodulatory Activities

Chronic inflammation is increasingly recognized as a fundamental contributor to the development of numerous non-communicable diseases, including obesity, Type 2 Diabetes (T2DM) mellitus, cardiovascular diseases, neurodegenerative disorders, inflammatory bowel disease, and cancer. Persistent activation of inflammatory signaling pathways results in excessive production of pro-inflammatory cytokines, oxidative stress, and progressive tissue damage. Consequently, naturally occurring anti-inflammatory compounds have become attractive candidates for disease prevention and complementary therapeutic interventions. Food-derived bioactive peptides have demonstrated remarkable anti-inflammatory properties through modulation of multiple cellular signaling pathways. Among these, inhibition of the NF-κB signaling pathway represents one of the best-characterized mechanisms. Under inflammatory conditions, activation of NF-κB stimulates the transcription of numerous pro-inflammatory mediators, including Tumor Necrosis Factor-Alpha (TNF-α), Interleukin-1 Beta (IL-1β), Interleukin-6 (IL-6), Cyclooxygenase-2 (COX-2), and inducible Nitric Oxide Synthase (iNOS). Numerous food-derived peptides suppress NF-κB activation, thereby reducing cytokine production and attenuating inflammatory responses [23].

In addition to NF-κB inhibition, several bioactive peptides regulate Mitogen-Activated Protein Kinase (MAPK) signaling pathways, including Extracellular Signal-Regulated Kinase (ERK), c-Jun N-Terminal Kinase (JNK), and p38 MAPK. Suppression of these signaling cascades contributes to decreased expression of inflammatory mediators while protecting tissues from chronic inflammatory injury. Furthermore, antioxidant peptides frequently exhibit indirect anti-inflammatory effects by reducing intracellular ROS, which serve as important upstream activators of inflammatory signaling pathways. Food-derived peptides also exert significant immunomodulatory activities by regulating both innate and adaptive immune responses. These peptides influence macrophage activation, dendritic cell maturation, natural killer cell function, and lymphocyte proliferation, thereby contributing to immune homeostasis. Several studies have demonstrated that specific peptides promote macrophage polarization toward the anti-inflammatory M2 phenotype while suppressing the pro-inflammatory M1 phenotype [22]. This immunoregulatory function is particularly important for controlling excessive inflammatory responses without inducing generalized immunosuppression. Milk-derived peptides remain among the most extensively investigated immunomodulatory compounds. Casein-derived peptides and lactoferrin-derived peptides have demonstrated the ability to regulate cytokine production, stimulate antibody responses, and enhance mucosal immunity. Likewise, peptides isolated from fish collagen, soy proteins, egg proteins, rice bran, and fermented food products have shown promising anti-inflammatory activities in both cellular and animal models. Increasing evidence also indicates that fermentation-derived peptides generated by lactic acid bacteria possess enhanced immunoregulatory properties owing to their unique peptide profiles. Another emerging area of research involves the interaction between bioactive peptides and the gut Microbiota. Certain peptides promote the growth of beneficial intestinal microorganisms while suppressing pathogenic bacteria, thereby contributing to improved intestinal barrier integrity and immune regulation. Through modulation of host Microbiota interactions, these peptides may exert systemic anti-inflammatory effects extending beyond the gastrointestinal tract [15], [22], [23]. Although substantial experimental evidence supports the anti-inflammatory and immunomodulatory properties of food-derived peptides, translation into clinical practice remains limited. Future investigations should emphasize well-designed human intervention studies, standardized peptide production protocols, pharmacokinetic evaluation, and long-term safety assessment. A deeper understanding of peptide receptor interactions and immune signaling networks will facilitate the development of peptide-based functional foods and therapeutic formulations targeting chronic inflammatory diseases [25].

5.5 Antidiabetic Activity

Diabetes mellitus, particularly T2DM, is one of the fastest-growing metabolic disorders worldwide and is characterized by chronic hyperglycemia resulting from impaired insulin secretion, insulin resistance, or a combination of both. Persistent hyperglycemia is associated with severe complications, including cardiovascular disease, nephropathy, retinopathy, neuropathy, and impaired wound healing. Consequently, considerable attention has been directed toward identifying naturally derived compounds capable of improving glucose homeostasis with minimal adverse effects [23]. Among these, food-derived bioactive peptides have emerged as promising candidates because of their ability to regulate multiple metabolic pathways involved in glucose metabolism. Unlike conventional antidiabetic drugs that generally target a single metabolic pathway, bioactive peptides often exhibit multifunctional mechanisms of action. Their antidiabetic effects include inhibition of carbohydrate-digesting enzymes, modulation of incretin metabolism, enhancement of insulin signaling, improvement of glucose uptake, attenuation of oxidative stress, and suppression of chronic inflammation. These complementary mechanisms may provide synergistic benefits in the prevention and management of T2DM. One of the best-characterized mechanisms involves inhibition of DPP-IV, a serine protease responsible for the rapid degradation of incretin hormones, particularly Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP). By inhibiting DPP-IV activity, bioactive peptides prolong the half-life of incretin hormones, thereby enhancing glucose-stimulated insulin secretion, suppressing glucagon release, delaying gastric emptying, and improving postprandial glucose regulation. Numerous peptides isolated from milk, fish, soy, oat, rice bran, and egg proteins have demonstrated potent DPP-IV inhibitory activity in both in vitro and animal studies. Another important mechanism involves inhibition of digestive enzymes responsible for carbohydrate hydrolysis, including α-amylase and α-glucosidase.

Suppression of these enzymes slows the digestion and absorption of dietary carbohydrates, thereby reducing postprandial blood glucose excursions. Several plant-derived peptides, particularly those obtained from soybean, pea, wheat, and rice proteins, have exhibited significant inhibitory effects against these enzymes, suggesting their potential incorporation into functional foods designed for glycemic control. Food-derived peptides have also been shown to improve insulin sensitivity through modulation of intracellular signaling pathways [30]. Activation of the Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/Akt) pathway promotes translocation of Glucose Transporter Type 4 (GLUT4) to the plasma membrane in skeletal muscle and adipose tissues, thereby enhancing glucose uptake. In addition, activation of AMP-Activated Protein Kinase (AMPK) contributes to improved glucose utilization, increased fatty acid oxidation, and reduced hepatic gluconeogenesis. These metabolic effects collectively improve insulin responsiveness and energy homeostasis [34]. Oxidative stress and chronic low-grade inflammation play central roles in the progression of insulin resistance and pancreatic β-cell dysfunction. Consequently, many antioxidants and anti-inflammatory peptides indirectly contribute to improved glycemic control by reducing ROS production, suppressing inflammatory cytokines, and protecting pancreatic β-cells against oxidative damage. Such multifunctionality distinguishes food-derived peptides from conventional glucose-lowering agents and supports their potential application as complementary nutritional interventions. Although numerous experimental studies have demonstrated promising antidiabetic activities, clinical evidence remains relatively limited. Future investigations should focus on improving peptide stability during gastrointestinal digestion, enhancing intestinal absorption through advanced delivery systems, and conducting well-designed human clinical trials to establish effective dosages and long-term therapeutic efficacy [30]. Nevertheless, current evidence strongly supports the potential of food-derived bioactive peptides as valuable functional ingredients for diabetes prevention and metabolic health management.

5.6 Anticancer Activity

Cancer remains one of the leading causes of morbidity and mortality worldwide despite substantial advances in diagnosis and treatment. Conventional therapeutic approaches, including chemotherapy and radiotherapy, are frequently associated with severe adverse effects, drug resistance, and limited selectivity toward malignant cells. Consequently, naturally occurring bioactive compounds capable of selectively targeting cancer cells while minimizing toxicity to normal tissues have attracted increasing scientific interest. Food-derived bioactive peptides have recently emerged as promising candidates owing to their diverse anticancer mechanisms and favorable safety profiles [2]. The anticancer activity of bioactive peptides is mediated through multiple molecular pathways that regulate tumor initiation, proliferation, angiogenesis, invasion, metastasis, and programmed cell death. Unlike many conventional chemotherapeutic agents, these peptides often influence several cellular targets simultaneously, thereby reducing the probability of therapeutic resistance. Their relatively small molecular size also facilitates interactions with cellular membranes and intracellular proteins involved in cancer progression. One of the most extensively investigated mechanisms is the induction of apoptosis. Numerous food-derived peptides activate intrinsic mitochondrial apoptotic pathways through modulation of Bcl-2 family proteins, increased mitochondrial membrane permeability, cytochrome c release, and subsequent activation of Caspase-9 and Caspase-3. Other peptides stimulate the extrinsic apoptotic pathway by activating death receptors located on the cell surface. Through these mechanisms, malignant cells undergo controlled programmed cell death without provoking excessive inflammatory responses [28]. In addition to apoptosis induction, several peptides inhibit uncontrolled cancer cell proliferation by arresting the cell cycle at the G0/G1, S, or G2/M phases. This effect is frequently associated with regulation of cyclins, Cyclin-Dependent Kinases (CDKs), and tumor suppressor proteins such as p53. Cell-cycle arrest prevents DNA replication and mitotic progression, thereby suppressing tumor growth and enhancing the susceptibility of cancer cells to other therapeutic interventions. Tumor angiogenesis represents another critical target of food-derived bioactive peptides. Several studies have demonstrated that specific peptides suppress Vascular Endothelial Growth Factor (VEGF) signaling, thereby inhibiting the formation of new blood vessels required for tumor growth and metastasis. Other peptides reduce cancer cell migration and invasion by regulating Matrix Metalloproteinases (MMPs), Epithelial–Mesenchymal Transition (EMT), and extracellular matrix remodeling. These effects collectively contribute to reduced metastatic potential and improved control of tumor progression. Accumulating evidence also suggests that bioactive peptides modulate intracellular signaling pathways involved in cancer development, including PI3K/Akt, MAPK, Wnt/β-catenin, NF-κB, and mTOR pathways. By regulating these signaling networks, peptides inhibit cellular proliferation, promote apoptosis, suppress inflammation, and reduce oxidative stress within the tumor microenvironment. Moreover, several antioxidant peptides indirectly contribute to cancer prevention by minimizing oxidative DNA damage and maintaining genomic stability.

Anticancer peptides have been identified from a wide variety of food proteins, including milk caseins, whey proteins, fish collagen, marine organisms, soybean, egg proteins, cereals, and edible insects. Marine-derived peptides have attracted particular attention because of their structural diversity and potent biological activities. Although most evidence currently originates from in vitro studies and animal models, several peptide candidates have demonstrated encouraging therapeutic potential for future pharmaceutical development [26]. Despite these promising findings, several obstacles continue to limit clinical application. Poor oral bioavailability, rapid enzymatic degradation, insufficient tumor-specific targeting, and large-scale production costs remain major challenges. Recent advances in peptide engineering, nanotechnology-based drug delivery systems, and peptide conjugation strategies are expected to overcome many of these limitations and accelerate the translation of food-derived anticancer peptides into clinical practice. The multifunctional biological activities of food-derived peptides, combined with their relatively low toxicity and natural origin, make them attractive candidates for complementary cancer prevention strategies and the development of next-generation peptide-based therapeutics. Continued interdisciplinary research integrating food science, molecular biology, biotechnology, and clinical medicine will be essential to fully exploit their therapeutic potential [31].

5.7 Other Emerging Biological Activities

Beyond their well-established antioxidant, antihypertensive, antimicrobial, anti-inflammatory, antidiabetic, and anticancer properties, food-derived bioactive peptides have demonstrated a wide range of additional biological activities that further expand their potential applications in functional foods, nutraceuticals, and pharmaceutical products. Advances in peptide discovery, high-throughput screening, and bioinformatics have accelerated the identification of multifunctional peptides capable of simultaneously modulating several physiological processes. These emerging activities highlight the versatility of food-derived peptides and support their development as natural health-promoting ingredients. The diverse biological functions of food-derived bioactive peptides are associated with distinct molecular mechanisms and depend strongly on peptide structure and food origin [23]. A schematic overview of the principal biological activities and their underlying molecular mechanisms is presented in Fig. 3, while a comprehensive summary of their representative food sources, mechanisms, and potential health applications is provided in Table 6.

6.1 Functional Foods and Nutraceuticals

One of the most important applications of food-derived bioactive peptides is their incorporation into functional foods and nutraceutical products. Peptide-enriched dairy products, protein beverages, fermented foods, dietary supplements, and fortified nutritional formulations have been developed to promote cardiovascular health, improve antioxidant capacity, regulate glucose metabolism, and support immune function. The increasing consumer preference for naturally derived health-promoting ingredients has further stimulated the commercialization of peptide-based functional products [31].

6.2 Pharmaceutical Applications

Food-derived peptides have attracted considerable attention as potential therapeutic agents or complementary treatments for chronic diseases. Their antihypertensive, antimicrobial, anti-inflammatory, antidiabetic, and anticancer properties provide opportunities for the development of peptide-based pharmaceuticals with improved safety profiles compared with many synthetic drugs. In addition, advances in nanotechnology and targeted drug delivery systems have enhanced peptide stability, bioavailability, and therapeutic efficacy, facilitating their translation into clinical applications [32].

6.3 Cosmetic and Personal Care Products

Bioactive peptides are increasingly incorporated into cosmetic formulations owing to their antioxidant, collagen-stimulating, anti-inflammatory, and skin-protective properties. Marine collagen peptides, milk-derived peptides, and plant-derived peptides have shown promising effects in improving skin hydration, reducing oxidative damage, promoting wound healing, and delaying signs of skin aging. Consequently, peptide-based ingredients have become important components of modern cosmeceutical products [33].

6.4 Food Preservation and Packaging

Natural antimicrobial and antioxidant peptides have emerged as promising alternatives to synthetic food preservatives. Their incorporation into edible coatings, biodegradable films, and active food packaging materials can inhibit microbial growth, reduce lipid oxidation, and extend the shelf life of food products while maintaining food quality and safety. Such applications also support the growing demand for clean-label and environmentally sustainable food preservation technologies [34].

6.5 Future Industrial Perspectives

Despite remarkable progress, the large-scale commercialization of food-derived bioactive peptides remains limited by challenges including production cost, peptide stability, gastrointestinal bioavailability, regulatory approval, and standardization of manufacturing processes. Future research should focus on integrating advanced bioprocessing technologies, AI-assisted peptide discovery, precision fermentation, and novel delivery systems to improve production efficiency and clinical effectiveness. These multidisciplinary approaches are expected to accelerate the translation of bioactive peptides from laboratory research to industrial and therapeutic applications [23].