Recent advances in bioactive peptides from fermented plant-based foods and their bioactivities

Abstract

Bioactive peptides (BAPs), which are protein fragments defined by their distinct structural features and amino acid sequences, impart health benefits to foods enriched with them. These benefits include antioxidant, antihypertensive, antidiabetic, and immunomodulatory properties. BAPs have emerged as potential substitutes for synthetic molecules in various applications. Nevertheless, there is inadequate of information on the production of BAPs via novel fermented plant-based foods (FPFs), and many BAPs resources in FPFs have not been effectively explored. This review extensively discussed recent trends in FPFs, ranging from vinegar, cheese liquor, fermented rice, etc., from 2019 to 2024. We further discuss the beneficial health impacts of BAPs derived from FPFs, factors affecting the bioavailability of bioactive peptides, trends, and future perspectives in bioactive compounds from fermentation foods. This review will add to the existing body of knowledge and improve our understanding of the potential of BAPs derived from fermented plant-based foods.

Graphical abstract

Highlights

• •Plant-based fermented foods’ (FPFs) peptides in the last 5 years were reviewed.
• •Bioactive peptides (BAPs) from FPFs show promise of therapeutic benefits.
• •FPFs are a direct and high-quality source for BAPs.
• •BAPs are potent, low-risk alternatives to synthetic ingredients in nutraceuticals and functional foods.
• •The current trends and future perspectives for BAPs from FPFs are discussed.

1. Introduction

The Food and Agriculture Organization (FAO) projected that by 2050, the world population is expected to reach close to 9 billion people (Garrido-Galand et al., 2021), with such an increase in population, the food industry and researchers have been focusing on the utilization of fermentation to improve human diet by further exploring efficient and sustainable alternatives to satisfy the demand on the food market (Rogers et al., 2024). Currently, people tend to believe that food contributes to health and that medical issues are closely related to the food consumed (Anosike et al., 2022). Since 8000 BC, fermentation has been used in human nutrition. Traditionally, fermentation has been used for food preservation, flavor improvement, and nutritional value addition (Rastogi et al., 2022). This method has been explored as an effective way to increase the synthesis of microbial metabolites with biological properties, utilizing a variety of substrates to accomplish various functional benefits such as antioxidant, antidiuretic, and antihypertensive actions (Sharma et al., 2020). Globally, fermented food accounts for approximately one-third of the food consumed and 20–40% (by weight) of individual diets (Campbell-Platt, 1994; Campbell-Platt, 2014).

Fermented plant-based foods encompass those derived from cereals, vegetables (sauerkraut), soy (miso and natto), etc. Notable secondary metabolites, including peptides, are produced during fermentation. These bioactive compounds exert several biological activities, among which are chronic disease prevention, such as cardiovascular diseases, diabetes, and cancer (Chang et al., 2025; Liang et al., 2023). Fermented food products, particularly those made from soy, chickpeas, and cereals, have been acknowledged in East and Southeast Asia as sizable food sources that have had a massive effect on dietary life (Romulo & Surya, 2021). Throughout fermentation, secondary metabolic pathways may result in the production of bioactive compounds or enzymes that liberate bioactive compounds from the substrate, which are beneficial to humans and animals (Durazzo et al., 2022).

Beneficial bioactive compounds from various meals, including bioactive peptides, impact biological functions and cellular activity, for instance treating metabolic disorders like hypertension, hyperglycemia, hyperlipidemia, and obesity (Chen et al., 2025; Li et al., 2023). Bioactive substances, such as antimicrobial peptides, act as secondary metabolites during fermentation. These substances include phenyl lactic acid and hydroxyphenyl acetic acid, indoleacetic acid, alcohols such as phenylethyl alcohol, and indoleacetic acid (Ma et al., 2024; Zhang et al., 2024). These bioactive substances significantly influence the bio-preservation of fermented food products such as cheese, beer, sourdough, and fermented vegetables (Guo et al., 2025). Enhancing the extraction of bioactive compounds and increasing their bioactivity in food has become a fascinating area of research for scientists in recent times (Tolve et al., 2021), not only for the health benefits of these bioactive compounds but also for their aromatic quality, which is known to affect the sensory and organoleptic qualities of food products, particularly the flavor and fragrance qualities of fermented plant-based foods (Sorrenti et al., 2023). Furthermore, it has been discovered that combining multiple bioactive compounds can produce a synergistic effect, resulting in greater bioactivity and functionality than a single component (Gao et al., 2022). A single micro-delivery system for probiotic strains and bioactive compounds in the targeted colon through food products has the potential to develop by this generally accepted idea in the pharmaceutical business (Shah et al., 2023). BAPs have emerged as potential substitutes for synthetic molecules in various applications, primarily due to their minimal adverse effects and significant value in the nutraceutical and functional food industry. Nevertheless, there is a lack of information on the production of BAPs via FPFs, and many BAPs resources in FPFs have not been effectively explored.

This review aims to condense the recent development of BAPs found in fermented plant-based foods (FPFs) in the last 5 years and assess the different progress in its bioactivity on human health nutrition by consuming these fermented plant-based foods. This review extensively discusses development in peptides FPFs, the beneficial health impacts of BAPs derived from FPFs, challenges in harnessing BAPs for the nutraceutical and functional food industries, factors affecting the bioavailability of bioactive peptides, and development. The researchers retrieved peer-reviewed articles from three databases: Scopus, Google Scholar, and PubMed, covering the period from January 2019 to 2024. (1) Scopus contains a comprehensive collection of abstracts and citations from scientific journals, conference proceedings, and books, and it is meticulously curated and covers contents that were the focus of this review; (2) Google Scholar grants access to a vast array of scientific literature from journals, conference proceedings, and books, and covers various subjects including bioactive peptides from plant-based fermented foods; (3) PubMed is well-known for its high-quality, comprehensive, and relevant. Furthermore, due to their extensive coverage and significance for bioactive peptides, specialized databases (PubMed) supplemented searches conducted on multidisciplinary research platforms such as Scopus and Google Scholar. The outlooks in bioactive compounds from fermented plant-based foods from 2019 to 2024 as shown in Fig 1 was done using lens.org that provides a detailed analysis of peptides obtained from fermented plant-based. The scholarly search keywords were “Plant-based fermented peptides (plant-based AND ferment AND peptides)”. There is an increasing trend in the number of publications regarding peptides obtained from fermented plant-based (Fig. 1A). Research on peptides obtained from fermented plant-based is mainly from biochemistry, biology, food science and chemistry disciplines (Fig. 1B), and reported by researchers in United States (23.6%), China (23.24%), India (11.02%), Germany (9.69%) and Korea (6.69%) (Fig. 1C). Keyword co-occurrence network map of related topics from RStudio bibliometrix analysis (Fig. 1D). This review will add to the existing body of knowledge and improve our understanding of the potential of BAPs derived from fermented food.

Fig. 1.

Publications related to “peptides from plant-based fermented foods according to the Lens.org database (A) Publications for the last five years (2019-2024) for topic of retrieval (B) Fields of studies (C) Countries active in the related studies and (D) Keyword co-occurrence network map of related topics on RStudio bibliometrix analysis.

2. Recent progress in fermented plant-based foods

2.1. Vinegar

Vinegar is one of the prominent FPFs in the world, specifically in Asian countries (Román-Camacho et al., 2023). Vinegar has been considered for taste enhancement in foods such as salad, ketchup, and different kinds of soup (Román-Camacho et al., 2023). Moreover, more research has shown vinegar to contain bioactive compounds that are nutritious and beneficial to health (Qing et al., 2023). In research by sun et al, it identified novel BAPs using RP-HPLC and nano-LC-MS/MS. Among the 710 peptides detected, four novel angiotensin-converting enzyme (ACE) inhibitors, VVPPGHPV, FPEQPP, FPPQQP, and YGRGPIE, demonstrated potent activity, with IC₅₀ values of 3.3 μM, 3.7 μM, 1.6 μM, and 5.9 μM, respectively. Notably, FPPQQP exhibited the most substantial ACE inhibitory effect, a finding further supported by molecular docking analysis, confirming its potential as a potent inhibitor (Sun et al., 2025).

Furthermore, another investigation focused on vinegar's impact on whole egg protein's antioxidant activity and structural characteristics. Vinegar treatment significantly enhanced hydrolysis in vinegar-treated egg liquid (VE) and its digested form (DVE), with DVE displaying notably more potent antioxidant activity. SDS-PAGE analysis confirmed greater gastrointestinal hydrolysis in VE compared to digested egg liquid (DEL), consistent with free amino acid data. FTIR analysis revealed structural transitions: VE1:3 proteins predominantly adopted β-sheet configurations, while DVE1:3 exhibited a higher proportion of α-helices and turns. This suggests vinegar treatment has great potential as a nonthermal processing method for promoting gastrointestinal digestion and producing superior antioxidant peptides (Qing et al., 2023). Lastly, using a combination of machine learning, AlphaFold2, and molecular dynamics, researchers identified six novel antimicrobial peptides (AMPs) from 98,539 metagenomic peptides in Shanxi aged vinegar. Among these, La-AMP, derived from Lactobacillus, displayed potent bactericidal activity against Escherichia coli and Staphylococcus aureus with high structural stability and no hemolytic effect. Mechanistic studies demonstrated that La-AMP irreversibly disrupted bacterial membranes, caused nucleic acid leakage, and induced ROS accumulation. Molecular simulations further revealed that La-AMP binds DNA gyrase through salt bridges, hydrogen bonding, and hydrophobic interactions, eventually triggering bacterial apoptosis (Cui et al., 2024).

2.2. Fermented rice

The ratio of intake of rice is considered to be globally high (Cáceres et al., 2019), inasmuch as the protein production ratio of rice is still low compared to other protein foods, fermented rice has more bioactive components that are beneficial to health (Moiseenko et al., 2024). Currently, rice-derived bioactive compounds are frequently used as active ingredients in cosmeceuticals, medicinal products, food additives, and healthy food products (Yang et al., 2025).

Recently, utilizing fermentation, probiotic start-up cultures such as LAB and Bacillus spp. are now used to increase the nutritional value by boosting the bioactive compounds in rice (Seong & Kim, 2021). When Limosilactobacillus reuteri was used to ferment brown rice, bioactive compounds such as antioxidant peptides exhibited considerable radical scavenging activity due to their low molecular mass and the presence of acidic, basic, aromatic, and hydrophobic amino acids, which may be the explanation for their significant antioxidant capacity and this according to Tyagi et al. (2023), possess an example of the practical dietary antioxidant used in functional foods to nurture human health.

Another investigation by Ding et al. (2024), focused on the antioxidant and anti-diabetic properties of rice wine lees protein hydrolysate (RWLPH) and its bioactive peptides. After simulated gastrointestinal digestion, the resulting RWLPH exhibited notable α-glucosidase inhibitory activity (IC₅₀ = 2.06 mg/mL) and antioxidant potential (DPPH: IC₅₀ = 1.27 mg/mL and ABTS: IC₅₀ = 0.33 mg/mL), alongside improved insulin resistance. 36 peptides, each five amino acids long and 500-750 Da in molecular weight, were identified. Notably, LLGDV and LGDEPL stood out, showing strong α-glucosidase inhibition (IC₅₀ ≈ 6.5 mM) and promoting a 35% increase in glucose uptake in insulin-resistant cells. Moreover, molecular docking simulations revealed that these peptides bind stably to α-glucosidase and insulin signaling proteins through hydrogen bonding, van der Waals forces and π-interactions, thus providing insight into their hypoglycemic mechanisms (Ding et al., 2024).

Likewise, Zheng et al. (2023) assessed BAPs from rice wine with both α-glucosidase inhibitory and antioxidant properties, while elucidating their underlying mechanisms. Peptide fractions obtained via macroporous resin chromatography were analyzed for bioactivities and composition. In silico screening followed by experimental validation, three novel peptides, QFTPR, FTYPR and SSLFR, were identified, with FTYPR exhibiting the highest activity. Molecular docking and dynamics analyses confirmed these peptides’ interactions with DPPH and ABTS radicals and the α-glucosidase active site via hydrogen bonds, π-stacking, and van der Waals interactions. These findings deepen our understanding of the bioactivities of rice wine and support its application as a functional product with added economic value (Zheng et al., 2023). In a separate study, hot water extraction of rice husks was optimized to produce a protein hydrolysate with enhanced anticancer activity. Under optimal conditions (2.0 mL/min flow rate, 60°C and pH 10.0), the yield reached 2.40 g/L protein (43.2 g/kg dried husk), the hydrolysate exhibited potent cytotoxic effects against A549 (IC₅₀: 1.98 μg/mL) and MCF7 cells (IC₅₀: 3.58 μg/mL), as confirmed by Hoechst staining, which revealed nuclear fragmentation and apoptotic body formation. The observed bioactivity is likely attributed to diverse peptides and protein subunits ranging from 10-180 kDa (Ilhan-Ayisigi et al., 2021). Additionally, six novel antioxidant peptides (MW ≤ 8 kDa) were isolated from fermented brown rice. These peptides ILTAV, AVPYPQ, NPIFDYVLLP, LGDVIGVP, VAPFPEV, and VLPVPK demonstrated strong in vitro radical scavenging capacities, with IC₅₀ values (μg/mL) ranging from 5.12 -12.54 (DPPH), 5.97 -14.20 (ABTS), 4.98 -12.19 (FRAP), and 9.71 -17.84 (PSC). These peptides also significantly reduced ROS levels in H₂O₂-treated Caco-2 cells. Furthermore, in silico analysis suggested strong binding affinity to the Keap1-Kelch domain, surpassing that of the reference ligand TX6, indicating a potential mechanism via the Keap1-Nrf2 antioxidant pathway (Tyagi et al., 2023).

2.3. Chinese liquor (baijiu)

Chinese liquor, known as baijiu, is a major globally recognized distilled spirit. Its value increases with age, and due to its unique production process, it holds significant economic importance in China with an annual production exceeding 10.7 billion liters (Tu et al., 2022). According to Tu et al. (2022), baijiu presents medicinal effects like getting rid of fatigue, cold, and phlegm-dampness when consumed in moderate quantities. Sorghum is used as the raw material for producing baijiu and, in other cases, as a blend of sorghum, millet, rice, corn, wheat, and sometimes peas. With the solid-state fermentation process, alongside ethanol (which happens to be the main product produced), some peptides are also produced. This is assumed mainly due to the rich protein content of the raw materials used. The baijiu peptides are cyclic, tripeptides, and tetrapeptides (Li et al., 2020).

Six novel peptides from baijiu were identified using HPLC-QTOF-MS, with concentrations ranging from 0.835 to 24.540 μg/L. Notably, their protective effects against 2,2'-Azobis(2-amidinopropane) dihydrochloride (AAPH)-induced oxidative stress in Human hepatocellular carcinoma cell line G2 (HepG2) cells were confirmed, as evidenced by reduced Reactive Oxygen Species (ROS) and Malondialdehyde (MDA) levels, along with increased levels of antioxidant enzymes [Catalase (CAT), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GSH-Px)] in a dose-dependent manner. Moreover, these antioxidant effects were associated with activating the Nrf2/ARE pathway, characterized by enhanced Nuclear factor erythroid 2-related factor 2 (Nrf2) activity and decreased ubiquitination (Huo et al., 2022). In a related investigation, using previously established methods, the antioxidant peptide VNP was isolated from Jiuzao, a byproduct of baijiu distillation. The in vivo antioxidant mechanism of VNP was evaluated in Sprague-Dawley rats subjected to AAPH-induced oxidative stress. Specifically, the study focused on the Nrf2/Keap1-p38MAPK/PI3K-MafK signaling pathway and related antioxidant enzymes (GPX1, CAT, SOD1, and HO-1). VNP, present at 5.25 mg/g in Jiuzao, significantly alleviated oxidative stress by activating these molecular pathways and enzymes (Jiang et al., 2021).

Jiang et al. (2021) developed a novel analytical method to screen and identify peptides in baijiu efficiently. This method employed magnetic solid-phase extraction using magnetic S-doped graphene (M-G-S), coupled with LC-MS. 28 peptides ranging from 3 to 9 amino acids in length were identified significantly more than those detected by traditional C18 adsorbents. Subsequently, six peptides were confirmed using synthetic standards based on retention time, MS/MS, and nuclear magnetic resonance analyses. Additionally, quantification through parallel reaction monitoring revealed concentrations between 1.14 and 10.25 ng/mL, with predicted antioxidant and ACE inhibitory effects (Jia et al., 2022).

2.4. Tempeh

Tempeh is a fermented cuisine derived primarily from soybeans that serves as a nutritious, cost-effective, and sustainable functional protein source. A recent study explored the protective effects of a glycine-rich peptide (GRP)T derived from fermented Chenopodium formosanum against non-replicative aging. Pretreating Hs68 cells with GRP before UVA exposure significantly reduced oxidative stress and enhanced cell viability. Transcriptomic analysis revealed that GRP upregulated genes linked to oxidative stress response and cell cycle regulation while activating the Nrf2 pathway and suppressing p53 and p21 expression. In Caenorhabditis elegans, GRP extended lifespan and improved oxidative stress resistance. Molecular docking simulations suggested that GRP may bind to the KEAP-BTB domain, potentially inhibiting a key enzyme and thereby activating the Nrf2 pathway (Hsieh et al., 2025). Another study explored the antitumor effects of soy-based tempeh extract (SBTE) and its peptide fractions on pancreatic (PANC-1) and colorectal (HT-29) cancer cells. Trypsin hydrolysis produced a novel peptide (P1: GENEEEDSGAIVTVK) alongside four dipeptides. Network pharmacology linked these peptides to 140 genes implicated in critical cancer pathways, such as the renin-angiotensin system, apoptosis, microRNA regulation, and cytokine signaling. The dipeptides demonstrated strong binding affinities to cancer-associated receptors, including PARP1 (ΔG: -6.5 kcal/mol) and EGFR (ΔG: -6.2 kcal/mol). In PANC-1 and HT-29 cells, the peptides markedly downregulated the expression of EGFR, iNOS, BIRC2, ANPEP, and PARP1 by tenfold (Lukman et al., 2025). A separate investigation examined the effects of fermentation and cooking on the protein quality and sensory characteristics of faba bean tempeh. Extended fermentation at elevated temperatures improved in vitro protein digestibility (IVPD) and produced a complete essential amino acid profile. While fermentation alone did not substantially reduce trypsin inhibitor activity (TIA), tempeh showed lower TIA levels compared to raw beans. Cooking had minimal impact on protein quality, and fermentation conditions did not significantly alter sensory attributes (Thulesen et al., 2025).

Peptides were extracted using ultrafiltration, gel filtration, and RP-HPLC, followed by LC-MS identification. Bioinformatics analyses confirmed peptide identities and functions. Although only a few peptides were common across all samples, Val-His and Ala-Leu-Glu-Pro were consistently present. Tempeh from high-sanitation producers contained a higher proportion of bioactive peptides (58%) compared to those from low-sanitation producers (35%) (Tamam et al., 2019). A computational study simulated enzymatic cleavage of soy proteins (glycinin and β-conglycinin) using the PeptideCutter tool. Simulation I (enzymes from Lactobacillus sp. and Rhizopus oligosporus) generated 58 peptides, compared to 41 in Simulation II (including Klebsiella pneumoniae enzymes). Three tripeptides Leu-Leu-Phe, Val-Val-Phe, and Arg-His-Lys were identified, with most cleaved peptides predicted to have antihypertensive and antidiabetic properties (Tamam et al., 2021). A study on Mucuna pruriens tempeh evaluated its ACE inhibitory activity during in vitro digestion and intestinal absorption. Fermentation for 72 hours (F72) yielded the highest ACE inhibition post-digestion, with no significant differences observed across intestinal segments (Windy et al., 2020). Lastly, an optimized process combining fermentation and papain hydrolysis was developed to produce bioactive peptides exhibiting antioxidant and ACE-inhibitory activities. Using an automated membrane reactor, optimal conditions ([E]/[S] = 10% w/v, 9-hour residence time, 10-kDa membrane) yielded an antioxidant capacity of 0.033 mg AEAC/mL and 50.9% ACE inhibition. Further filtration with a 2-kDa membrane enhanced ACE inhibition, reducing the IC50 by approximately 40% (Sitanggang et al., 2021).

2.5. Natto

Natto is a soybean product fermented by natto bacteria. In a research by Wu et al. (2024), the authorsexplored the effects of fermenting soymilk using Bacillus natto, Propionibacterium shermanii, and traditional milk fermenters on its texture, polyphenol content, and protein digestibility. Co-fermentation with B. natto or P. shermanii significantly increased levels of key bioactive compounds, including gallic acid, caffeic acid, and γ-aminobutyric acid, while also improving protein digestibility. Peptidomic analysis showed that the combination of P. shermanii and Lactobacillus plantarum produced the highest yield of bioactive peptides. In contrast, co-fermentation of B. natto with Streptococcus thermophilus resulted in a more diverse peptide profile, primarily derived from glycine-rich protein, β-conglycinin alpha subunit 1, and ACB domain-containing proteins (Wu et al., 2024). A separate investigation explored the LPS-neutralizing and angiogenic effects of cationic peptides from Natto, a Japanese fermented soybean product. Following the separation of Natto extract into 20 fractions by autofocusing, 13 cationic peptides were purified and identified from the highly alkaline (pH >12) fractions. Seven peptides (pI >9.5) were synthesized and tested. In LPS-neutralization assays, they showed 50% effective concentrations of 2.6-5.5 μM. Six peptides also promoted angiogenesis (23-31% increase in tube formation at 10 μM), except GEIPRPRPRPQHPE. None exhibited hemolytic activity (up to 500 μM). These findings suggest that six Natto-derived cationic peptides possess dual LPS-neutralizing and angiogenic properties without hemolysis (Taniguchi et al., 2019). Another study examined soybean fermentation in a saccharified corn steep liquor (CS medium using Bacillus natto GUTU09 (B9) alongside Bifidobacterium animalis subsp. lactis strains BLH1 or BLH6 to produce CS-natto. Physicochemical and functional analyses revealed that fermentation significantly enhanced natural killer (NK) cell activity peaking at 425.00 FU/g in the BLH6-B9 natto and antioxidant capacity. Co-fermentation increased levels of phenolic compounds, organic acids, soy isoflavones, amino peptide nitrogen, and soluble peptides. Additionally, Bifidobacterium strains improved the fermentation efficiency of B. natto. Correlation analyses indicated that Bifidobacterium may stimulate NK cell activity, BLH1 promotes organic acid conversion, and there is potential interconversion between daidzein and daidzin (P < 0.01). Sensory evaluation using an electronic tongue confirmed improved taste profiles in co-fermented CS-natto (Zhao et al., 2024).

2.6. Other plant-based

Over the years, cereals have been reported as one of the best foods that add nutritional value to family meals around the globe, especially in the Sahara and sub-Saharan African countries, as they contain a considerable quantity of starch, phenolic components, and other bioactive compounds that make them a healthy food choice (Banwo et al., 2021). The production of the hydrolytic activity of enzymes during the fermentation process increases the dissipation of the cell wall, leading to an increase in bioaccessibility of bioactives in the cereals (Nemes et al., 2022).

In a related study, defatted wheat germ meal processing was optimized through three pretreatment strategies: microwave, alkali extraction-acid precipitation, and ultrasonic-assisted enzymatic hydrolysis, followed by fermentation using Bacillus subtilis and Angel yeast. Among these, ultrasonic-assisted enzymatic hydrolysis emerged as the most effective, significantly reducing total and reducing sugars while improving microbial accessibility by disrupting starch and surface structures. Consequently, fermentation with B. subtilis led to superior outcomes, including a 139.72% increase in soluble proteins, yields of 0.37 mg/mL polypeptides and 0.63 mg/mL phenolics, and a 10-fold increase in γ-aminobutyric acid. Structural modifications characterized by multi-fault and cave-like surfaces, along with improved antioxidant properties, confirmed the efficacy of ultrasonic pretreatment. Thus, this approach offers a promising method for converting wheat germ meal into high-value functional nutrients, contributing to sustainable byproduct valorization (Pan et al., 2025).

A novel fermented pistachio beverage was also developed using selected LAB, namely Companilactobacillus paralimentarius and Leuconostoc pseudomesenteroides. Proteolytic activity was assessed through physico-chemical, microbiological, peptidomic, and proteomic analyses following 24 hours of fermentation. Both non-inoculated and acidified samples served as controls. Remarkably, hundreds of peptides derived from 2S albumin, 11S, and 7S globulins were identified, with the highest abundance found in Leuconostoc-fermented samples. Indeed, the proteolytic systems of LAB, in conjunction with endogenous seed proteases, likely contributed to this rich peptide profile. Among the identified peptides, 31 were classified as bioactive, demonstrating antioxidant, ACE-inhibitory, and Dipeptidyl Peptidase IV (DPP-IV)-inhibitory functions, predominantly in Leuconostoc samples. Accordingly, this study highlights the feasibility of developing functional pistachio-based beverages with significant health-promoting properties (Marulo et al., 2024).

Finally, Akan et al. (2023) explored the influence of fermentation and food matrix, specifically drink versus yogurt consistencies, on ACE-inhibitory peptides, protein composition, and β-glucan levels in oat-based products. Oat-to-water ratios were adjusted (1:3 for yogurt; 1:5 for drinks), and fermentation was carried out using yogurt cultures and Lactobacillus plantarum, maintaining viability levels above 10⁷ CFU/g. Post-digestion analyses indicated greater protein hydrolysis in drink-consistency products (82.06%) compared to yogurt (57.70%) (p < 0.05). SDS-PAGE analysis identified 12-15 kDa and ∼35 kDa protein bands before digestion, with the 35 kDa bands disappearing after gastric processing. ACE-inhibitory activity in peptide fractions of <2 kDa and 2-5 kDa ranged from 46.93% to 65.91%, with fermentation significantly boosting activity in the <2 kDa group (p < 0.05).

3. Health benefits of bioactive peptides

BAPs, derived from FPFs, exerts several health benefits, including antibacterial, antihypertensive, antioxidant, antidiabetic, immunomodulatory, and anticancer once it reaches the target organs (Bhuva et al., 2025). The following subsections extensively discuss various significant peptide bioactivities related to structural and physicochemical characteristics.

3.1. Antidiabetic activity

Type 2 diabetes mellitus is one of the health issues with the fastest global spread, affecting both developed and developing nations. Biguanides, thiazolidinediones, gliptins, and sulfonylureas are some of the synthetic antidiabetic drugs that are currently available in the market; however, side effects such as nausea, diarrhea, hypoglycemia, flatulence, and abdominal cramping have sparked the quest for novel natural antidiabetic treatment options (Valenzuela Zamudio et al., 2022). The development of natural therapies with no side effects and the demonstration of antidiabetic action by BAPs from FPFs have been researched. Table 1 shows the antidiabetic activities of FPFs.

Table 1.

Antidiabetic activities of fermented plant-based foods.

Sources	Peptides	α-Amylase	α-Glucosidase	DPP-IV	Reference
Soybean	IKSQSES and NNDDRDS	85%	25%	IC50: 0.8 mg/mL	(Ramos & Kempka, 2024; Wen, Zhang, Feng, et al., 2020)
Lupin	LTFPGSAED	20%	21%	IC50:0.75 mg/mL	(Ramos & Kempka, 2024; Wen, Zhang, Feng, et al., 2020)
Common bean	LAPPG and KLLLRRLQ	5%	30%	IC50:0.60 mg/mL	(Ramos & Kempka, 2024; Wen, Zhang, Feng, et al., 2020)
Black bean	ATNPLF and AKSPLF	30%	49%	IC50:0.87 mg/mL	(Ramos & Kempka, 2024; Wen, Zhang, Feng, et al., 2020)
Pinto bean	PLPWGAGF and PPHMLP	62%	NR	-	(Ramos & Kempka, 2024; Wen, Zhang, Zhang, et al., 2020)
Oat protein	DVVALPAG and GDVVALPA	57%	78%	IC50:0.413 mg/mL	(Ramos & Kempka, 2024; Wen, Zhang, Zhang, et al., 2020)
Hard-to-cook bean	NEGEAH, LLSL and QQEG	49%	76%	55%	(Ramos & Kempka, 2024; Wen, Zhang, Zhang, et al., 2020)
Chenopodium quinoa Wild.	DKDYPK, IQAEGGLT and GEHGSDGNV	IC50: 0.48 mg/mL	IC50: 0.32 mg/mL	IC50: 1.64 mg/mL	(Ramos & Kempka, 2024; Wen, Zhang, Zhang, et al., 2020)

According to do do Prado et al. (2022), bioactive peptide-enriched FPFs have anti-diabetic properties, as soy-derived peptides released during meju production increase insulin sensitivity and insulinotropic effects. A recent study shows that soy-based fermented food known as hawaijar exhibited therapeutic benefits like underlying antidiabetic effects, probably due to its high content of BAPs of 24 kDa (Das et al., 2023). Numerous investigations have documented the identification of peptides that may inhibit the activities of dipeptidyl peptidase-IV (DPP-IV), which is a critical therapeutic target for the management of diabetes (Jin et al., 2021; Kęska & Stadnik, 2021; Wang et al., 2021). Dipeptidyl peptidase-IV, a serine protease, catalyzes the rapid hydrolysis of incretin hormones, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, prolonging the active state of these hormones. Dipeptidyl peptidase-IV inhibition raises insulin release, ultimately lowering blood glucose levels (Valenzuela Zamudio et al., 2022). The catalytic site of dipeptidyl peptidase-IV consists of two significant binding pockets, primarily hydrophobic residues (Mourad et al., 2021). Y666, S630, V656, W659, Y547, Y631, H740, Y662, N710, V711, E206, R125, and E205 are some of the residues that make up the active site according to Mourad et al. (2021). These candidate peptides may effectively block dipeptidyl peptidase-IV when they bind to these active site residues, exhibiting the peptide's antidiabetic effects. The YPSYGL (an ACE-inhibitor peptide), produced during the fermentation of milk using L. lactis, significantly inhibited dipeptidyl peptidase-IV, demonstrating its multifunctional role in preventing cardiovascular disease (CVD) (Rendón-Rosales et al., 2022). Two putative dipeptidyl peptidase-IV inhibiting peptides, FKRPPL and WTIAVPGPPHS, were found in dry-cured pork loins. In an in-silico research, the peptides showed favorable absorption, distribution, metabolism, excretion, and toxicity functions, which raises the possibility of producing dipeptidyl peptidase-IV inhibitory nutraceuticals from dietary peptides (Kęska & Stadnik, 2021). Extensive research on these subjects could also lead to the discovery of novel multifunctional peptides that can be used to develop nutraceuticals for the prevention of diabetes and hypertension, as well as the identification of dipeptidyl peptidase-IV and ACE inhibitory peptides, resulting in effective preventive therapeutics against CVD.

Despite compelling evidence that BAPs from FPFs possess antidiabetic properties, significant obstacles prevent their clinical application. Current research is predominantly based on in vitro and in silico models, which cannot fully replicate the complexity of human metabolism. Furthermore, the reproducibility of BAPs is complicated by variations in fermentation processes and food compositions, and their stability during human digestion remains poorly understood. To advance the field, future efforts must prioritize in vivo and clinical trials to confirm efficacy and safety in humans. Utilizing advanced analytical tools will also be crucial for clarifying structure-activity relationships and discovering multifunctional peptides. Ultimately, interdisciplinary collaboration is essential to standardize production, overcome existing challenges, and successfully develop these natural compounds into reliable therapies for diabetes management.

3.2. Immunomodulatory and anti-inflammatory activity

Immunomodulatory peptides are employed in several sectors, including the cosmetics, food, and pharmaceutical industries. They constitute the most intricate and diverse BAPs (Pavlicevic et al., 2022). Immunomodulation is a broad concept that encompasses modifications to adaptive and/or innate immunity and oxidative stress (Pavlicevic et al., 2022). Immunomodulatory peptides can be categorized as immunosuppressive or immunostimulatory depending on how they affect the immune system, which then leads to additional classifications of peptides as cytoprotective/cytotoxic, antiproliferative/proinflammatory, and proinflammatory/anti-inflammatory depending on the peptide activity (Pavlicevic et al., 2022).

Numerous FPFs have peptides with various immunomodulatory effects, emphasizing the industrial potential of these BAPs (Fu et al., 2021; Ma, Wang, et al., 2021; Nielsen et al., 2022). Fermented lupin from a recent study where L. plantarum and L. reuteri were used in whole-grain lupin proteolysis exhibited antiproliferative and radical scavenging activities against cancer cell lines, suggesting that immunomodulatory peptides with multiple functions were released (Ayyash et al., 2019). It is well-known that proinflammatory and anti-inflammatory peptides exert their biological activities through the regulation of certain interleukins (such as IL4, IL2, IL1β, IL10, IL6) and cytokines such as necrosis factor α (TNFα), and interferon γ (IFNγ) (Pavlicevic et al., 2022). Immunomodulatory peptides regulate cellular activities, which interfere with signal transduction by altering the level of adhesion molecules on monocyte and leukocyte membranes, as well as neutrophil aggregation inhibition and cytosolic calcium ion concentrations modulation (Pavlicevic et al., 2022). The proteolytic processes in fermenting microbial strains greatly influence the production of diverse immunomodulatory peptides with anti-inflammatory characteristics in FPFs. Peptides originating from soybeans, such as lunasin (SKWQHQQDSCRKQLQGVNLTPCEKHIMEKIQGRGDDDDDDDDD) and soymetide (MITLAIPVN), influence macrophage phagocytosis by stimulating human polymorphonuclear leukocyte activity (Paterson et al., 2023).

Lunasin-derived peptides, RKQLQGVN and GRGDDDDDDDDD, demonstrated anti-proliferative and anticancer effects against colorectal cancer cells, highlighting the potential of fermented soybean for generating immunomodulatory peptides (Pavlicevic et al., 2022). Despite the potency of natural immunomodulatory peptides as alternatives to synthetic counterparts, in vivo evaluation has revealed side effects, including mild allergic reactions (Ashaolu et al., 2024).

To ensure the development of safe functional foods and nutraceuticals, it is imperative to exclude toxic, allergenic, or mutagenic peptides. Rigorous in vivo assessment of peptides derived from FPFs is crucial before considering them for nutraceutical production. Artificially designed peptides also find applications in anticancer drug development. For instance, Cyclo-GCGPep1, a cyclic peptide, was created for the development of a human epidermal growth factor receptor 2 (HER2)-targeting peptide drug conjugate, displaying potent anticancer activity (Chai et al., 2022; Zhou et al., 2021). Additionally, a novel self-assembling, cell-penetrating artificial peptide, RRRRRRSHPRSNSGSGKLVFFAE, was designed to inhibit Akt1 for thyroid cancer therapy (Chai et al., 2022).

Bioactive compounds contained in fermented food, mainly polyphenols, have shown the capability to suppress the secretion of cytokines that cause inflammation and provide anti-inflammatory responses (Caban & Lewandowska, 2022). Fermented fish and vegetables are known for their nutritive aspects and high-value addition to the human diet, but with recent research, it was also found that the bioactive compounds contained have anti-oxidative and anti-inflammatory activities (Okeke et al., 2021). Through fermentation, numerous bioactive compounds in soy food, including isoflavones, vitamins, peptides, and amines that are at the root of the anti-inflammatory activity, are increased (Jang et al., 2021). The application of solid-state fermentation (SSF) was employed on rosebay willowherb, which demonstrated anti-inflammatory activity and reduced many other health-related diseases on account of bioactive compounds found in it (Jariene et al., 2020).

Shan et al. (2025) focused on the functional enhancement of hemp seeds (HS) through Lactiplantibacillus plantarum fermentation. Fermented (FHS) and unfermented HS extracts were assessed for anti-inflammatory properties via cell-based assays. Significantly, the 70% ethanol extract of FHS showed marked inhibition of cytokines (TNF-α, IL-1β, IL-10), with fermentation increasing suppression by 25%, 39.3%, and 29.6%, respectively, compared to unfermented samples. Moreover, mRNA analysis confirmed FHS’s immunomodulatory capabilities. Correspondingly, metabolomics revealed enrichment in pathways such as nicotine addiction, antifolate resistance, D-amino acid metabolism and aminoacyl-tRNA biosynthesis, each correlating with the observed biological effects. Additionally, FHS extended the survival of pathogen-exposed C. elegans while modulating innate immunity genes (lys-1, gcs-1, pmk-1, dbl-1, elt-2, and dod-22). Notably, five novel BAPs (AAELIGVP, AAVPYPQ, VFPEVAP, DVIGVPLG, PVPKVL) were identified as fermentation products, which strongly correlated with enhanced anti-inflammatory and immune-supportive functions (Shan et al., 2025).

While bioactive peptides from FPFs show promising immunomodulatory potential, significant challenges remain. Current research relies heavily on in vitro studies, which fail to account for issues like low bioavailability and peptide degradation in vivo. Safety concerns, including allergenicity, and inconsistent production due to variable fermentation processes, also hinder progress. Confirming efficacy and safety through large-scale trials must be a priority Integrating advanced tools like metabolomics and bioinformatics can clarify mechanisms of action. Employing precision fermentation and protein engineering could yield more stable, targeted peptides. Cross-disciplinary collaboration is essential to develop safe, standardized, and effective peptide-based functional foods and nutraceuticals for clinical use.

3.3. Antioxidant activity

An unhealthy way of life, including habits like consuming processed foods, smoking cigarettes, and exposure to industrial chemicals, pollutants, and radiation, leads to an excessive generation of free radicals within the body. This excess accumulation of free radicals gives rise to oxidative stress, according to He, Yang, et al. (2019). Various oxidative stress-related cell actions, including peroxidation of membrane lipids and the breakdown of structural proteins, nucleic acids, and enzymes, enhance the risk of developing CVD (hypertension and diabetes) and cancer (He, Yang, et al., 2019). Due to antioxidant peptides, FPFs consumption has been linked to the neutralization of ROS, prevention of lipid peroxidation, chelation of metal ions, and free radical scavenging (Begunova et al., 2021). The antioxidant effects of a peptide are closely linked to the hydrophobic amino acids, such as His, Trp, Tyr, and Pro; the release of such peptides depends on the specificity of the fermenting starter strain (Sanjukta et al., 2021).

In research done on fermented food, antioxidant activity has proven to be a prominent function among many others offered by these kinds of food, and Table 2 shows the antioxidant peptides from plant sources. However, it is still a challenge to enhance the antioxidant activity of some fermented foods, such as fermented legumes, while an investigation done by Sarıtaş et al. (2024), the antioxidant activities of solid fermented lentils varied depending on the strain employed during fermentation: in the two strains utilized, Aspergillus niger strain proved to enhance the antioxidant activities of lentil compared to when fermented using Aspergillus oryzae (Magro et al., 2019).

Table 2.

Peptides from plant protein with antioxidant activity.

Sources	Antioxidative peptides sequence	Activity (IC50)	References
Black soybean	RDPEER, IVPK, LIVPK, and YSK,	0.216 μM	(Wen, Zhang, Feng, et al., 2020)
Kinema	CHMYWF, SEDDVFVIPAAYPF, and VLLY	3 mM/mL	(Ma et al., 2020)
Walnut meal	QQRQQQGL, VEGNLQVLRPR, YVPHWDL and WSREEQEREE	0.173 μM/mL	(Sheng et al., 2019); (Wang et al., 2016)
Soybean cheese	AVPYPQR, KFVPKQPNMIL, EMPFPK, VLPVPQK, and KELEEK	0.216 μM/mL	(Wen, Zhang, Zhang, et al., 2020)
Rice bran	TVAQGEGVVA,	0.62 μM	(Zaky et al., 2019)
Soy protein isolate	FESFL, WNLNAN, SLLDFPALW, and LDDDGRL	0.54 μM/mL	(Wen, Zhang, Feng, et al., 2020)
Wheat germ	TVGGAPAGRIVMQ, AREGETVVPG	0.5 mg/mL	(Feng et al., 2019)
Quinoa	DKDTPK, LWREGM, and IFQETI	9.80 μg/mL	(Mudgil et al., 2019)
Mulberry leaf	SVL, EAVQ, RDY, KWFCT	1.09 mg/mL	(Sun et al., 2019)
Oat bran	WGYDGDAPVVA, EARQIEPKRA, LHGQFPI	0.13 μM/mL	(Esfandi et al., 2019)
Wheat gluten	OY, LY, YQ, RGGY, APY, and YQAPSY	0.31 mM/L	(Liu, Li, et al., 2021)
Amaranth seed	PKLTL and LVRW	0.26 μM/L	(Ayala-Niño et al., 2019)
Palm kernel cake	WAFS, YLLLK, KVFLGLK, YGIKVGYAIP, and GVQQGAGHYALL	4 mg/mL	(Arulrajah et al., 2020)

In a recent research, fermented soy food showed advanced polyphenolic components with an elevated antioxidant profile, with some compounds such as 3’-hydroxydaidzein, which presented with high DPPH free radical scavenging as well as ABTS assay as a result of β-glycosidase activity (Jayachandran & Xu, 2019). Furthermore, the free amino acids and peptides increased during the aerobic fermentation with Rhizopus, with a concurrent increase in antioxidant activity in the water-soluble fraction, indicating that the amino acids and peptides formed during fermentation are responsible for the antioxidant activity in the fermented tempeh (Jang et al., 2021).

In addition to radical scavenging peptides, FPFs offers the potential for identifying regulatory antioxidant peptides that can inhibit the generation of free radicals within the body through biochemical mechanisms (Lv et al., 2022). The excessive activation of the myeloperoxidase (MPO) pathway leads to an increased release of the free radical HOCl, which has been implicated in the pathogenesis of various disorders, including atherosclerosis, diabetes, premature aging, and arthritis (Frangie & Daher, 2022). The peptide SEDDVFVIPAAYPF, which is derived from Bacillus licheniformis fermented kinema (a sticky, fermented soybean food), was subjected to in-silico analysis to investigate its binding affinity with myeloperoxidase (MPO). The molecular docking results revealed a robust contact between the peptide and the catalytic residues of the MPO enzyme, indicating the potential inhibitory activity of the peptide against MPO (Sanjukta et al., 2021). Investigating peptidomics in FPFs has the potential to discover hitherto unidentified antioxidant peptides, which can be utilized in manufacturing potent nutraceuticals and developing novel functional food products. Nevertheless, it is crucial to conduct comprehensive research on the bioavailability and resistance of antioxidant peptides to gastrointestinal hydrolysis and hydrolysis by specific enzymes to determine their suitability for application in the functional food sector.

Although FPFs have known antioxidant properties, they remain significantly under-researched. Current findings are often inconsistent due to variations in fermentation methods, and most data comes from in vitro studies, which fail to capture the complex human body. A key limitation is the unknown bioavailability, stability, and metabolic fate of antioxidant peptides after digestion. To advance the field, future research must prioritize in vivo and clinical trials to confirm these health effects. Employing advanced techniques like peptidomics will be crucial for identifying the structure and mechanisms of bioactive peptides. Ultimately, optimizing fermentation processes and fostering multidisciplinary collaboration are essential to successfully translate these promising properties into tangible nutraceuticals and functional foods for human health.

3.4. Antimicrobial effect

Several studies have demonstrated that BAPs from fermented food exhibited excellent antimicrobial properties. The antimicrobial peptide APT was derived from Lactobacillus ALAC-4, which was obtained from a traditional fermented sour porridge. This particular strain has demonstrated the ability to inhibit a wide range of foodborne pathogenic bacteria, with notable efficacy against Candida albicans (Dong et al., 2024). An additional examination of the antibacterial mechanism utilizing Candida albicans as the indicator strain has unveiled that APT has the potential to hinder the growth of Candida albicans through four distinct mechanisms. These mechanisms include the cell wall disruption, the reduction of phosphonic acid metabolism, the augmentation of cell membrane permeability, and the diminishment of respiratory enzyme activity within the strain (Wang et al., 2022). Antimicrobial peptide F1 was a recently discovered peptide derived from Lactobacillus paracasei subsp. In some countries like India, fermented onions are consumed as porridge and have been substantiated to have antibacterial activity. Studies have shown that small onions (Allium parvum) and big onions (Allium cepa) present bioactive peptides, which hinder the protein synthesis of bacteria and their growth (Etikala et al., 2022). One study sought to investigate the effect of SSF of Mexican oregano Lippia graveolens, Byrichoderma harzanium, and Rhizopus oryzae strains and reported significant antimicrobial activities, which mainly were a result of the BAPs and phenolic compounds produced during the process (Bautista-Hernández et al., 2022).

Similarly, another study successfully isolated two AMPs, BAP I and BAP III, from Lactobacillus species using gel filtration chromatography. Their molecular weights (4168.14 Da and 8076.45 Da) were confirmed via MALDI-TOF MS and SDS-PAGE. Both peptides displayed strong antibacterial activity, particularly against Pseudomonas aeruginosa and Staphylococcus aureus. Notably, BAP I was more effective, likely due to its amphipathic structure and hydrophobic C-terminal region, which disrupted bacterial membranes, as confirmed by SEM imaging. Additionally, both peptides inhibited bacterial Deoxyribonucleic Acid polymerase, decreasing Polymerase Chain Reaction (PCR) product formation. Circular dichroism (CD) spectroscopy revealed peptide-induced conformational shifts in Taq polymerase, resulting in increased flexibility. Molecular docking and dynamics simulations supported a dual-action mechanism involving membrane disruption and DNA replication interference, positioning BAP I and BAP III as promising candidates against multidrug-resistant infections (Niknam et al., 2025).

Significant hurdles persist for antimicrobial peptides from FPFs, despite encouraging evidence. Most studies are confined to lab settings, failing to prove stability or efficacy in real foods or the human body. Inconsistent fermentation processes and extraction methods also create variable results, while the structural details and mechanisms of these peptides are often unclear. Future progress depends on validating their safety and efficacy through in vivo studies. Leveraging advanced tools like omics and molecular modeling can elucidate their modes of action, paving the way for designing more potent synthetic versions. While the goal of integrating these peptides into functional foods or natural preservatives is promising, achieving it requires a multidisciplinary effort to overcome critical regulatory, scalability, and sensory acceptance hurdles.

3.5. Antihypertensive activities

The prevalence of hypertension is rising annually, with a growing number of individuals being diagnosed due to factors such as increased stress levels, increased financial strain, and decreased quality of life (Tamura et al., 2022). Synthetic medications have been linked to several adverse reactions, including skin rashes, hypotension, and angioedema. The BAPs derived from various FPFs possess ACE inhibitory activity. These peptides are generated by the hydrolysis of the parent protein by the microbial strains involved in the fermentation process (Xue et al., 2021). FPFs have demonstrated their efficacy as valuable sources of ACE-inhibitory peptides. The peptides derived from these sources have the potential to be utilized in the prevention of hypertension, offering a distinct advantage over synthetic pharmaceuticals due to their absence of documented side effects. The ACE-inhibitory action of a peptide is correlated with the existence of particular amino acids at a designated sequence position of the peptide (Wang & Zhou, 2020).

The process of soybean fermentation through the utilization of Enterococcus faecium led to the production of several peptides, including VF, PLVV, LP, VPL, and IL, which have demonstrated potential in inhibiting ACE activity (Daliri et al., 2021). Additionally, fermented soybean contains around 145 bioactive components, including peptides, phenolic compounds, antioxidants, and essential fatty acids, which contribute to its antihypertensive properties (Daliri et al., 2021), as a result of BAPs reducing the intensity of the renin-angiotensin system (RAS) and regulating the secretion balance of Endothelin-1 (ET-1) and nitric oxide (NO) to ensure the better function of endothelia and ameliorate the intestinal flora (Song et al., 2021). Using computational methods to analyze peptides based on their residue position and composition has proven to be a cost-effective and efficient approach to identifying ACE-inhibitory peptides derived from fermented food products. The peptides produced from FPFs have the potential to be considered viable options for the development of nutraceuticals with antihypertensive properties.

Grape pomace and wine lees protein isolates were evaluated as potential sources of antihypertensive BAPs through enzymatic hydrolysis. Notably, hydrolysates fractionated via ultrafiltration demonstrated higher ACE inhibitory activity, particularly in Flavourzyme-treated grape pomace and Alcalase-treated wine lees. Subsequently, their <3 kDa fractions were further purified using semi-preparative reversed-phase chromatography. Peptidome analysis via nano-LC-Orbitrap MS/MS enabled the identification of peptides associated with bioactivity. Specifically, characteristics such as hydrophobicity and the presence of ACE-inhibitory peptide motifs, namely di-, tri, and tetrapeptides, were found to correlate with antihypertensive effects. Among these, peptides including GPCKFYYGK, FSSFYYGK, and YYGKF were highlighted as major contributors to the observed activity (Fontana et al., 2025). Meanwhile, duckweed, a protein-rich aquatic plant, has also shown promise as a novel source of bioactive peptides. However, identifying peptides within its complex mixtures remains a significant challenge. To address this, enzymatic hydrolysis using enzymes such as pepsin and chymotrypsin was employed, followed by centrifugation to produce two fractions: the supernatant (DS) and the pellet (DP). Among these, DS fractions, especially those digested with pepsin, exhibited potent bioactivities, with IC₅₀ values of 0.7 mg/mL for dipeptidyl peptidase-IV (DPP-IV) inhibition and 0.07 mg/mL for ACE inhibition. Furthermore, the combination of Partial Least Squares Discriminant Analysis (PLS-DA) and Quantitative Structure-Activity Relationship (QSAR) modeling led to the identification of five novel dipeptidyl peptidase-IV (DPP-IV) inhibitors (notably Active Pharmaceutical Ingredient (API), with an IC₅₀ of 126.88 μM), eleven ACE inhibitors (highlighted by Feature Activity Relationship (FAR), with an IC₅₀ of 13.54 μM), and four antioxidants (each >200 μM). Remarkably, two peptides demonstrated multitarget activity across all three bioactivities, emphasizing their potential therapeutic relevance (Cournoyer et al., 2025).

Research into antihypertensive peptides from FPFs faces key hurdles. Inconsistent fermentation and processing create variable results, while a reliance on in vitro data leaves human bioavailability and efficacy unclear. Isolating specific peptides from complex mixtures is also technically challenging. Future work must prioritize in vivo and clinical studies to confirm safety and efficacy. Advanced tools like machine learning and multi-omics can help predict and optimize peptide activity. Finally, developing cost-effective production and encapsulation methods is crucial for industrial application. Bridging this lab-to-clinic gap is the essential next step for these promising natural compounds.

Other ACE inhibitory peptides derived from fermented plant-based food products are shown in Table 3.

Table 3.

Inhibitor peptides from fermented plant foods.

Renin and ACE inhibitor peptides derived from plant foods
Source	Inhibitor Peptides	Activity (IC50)	References
Porphyra yezoensis	IQP, PYGP, and PPY	0.41 mM	(Nardo et al., 2020)
Rapeseed	RALP, GHS, RIY and TNLDWY	1.932 mM	(Ma et al., 2019)
Moringa oleifera leaf	LGFF andGLFF	1.88 mM 2.80 mM	(Ma, Li, et al., 2021)
Amaranth proteins	SFNLPILR, FNLPILR and AFEDGFEWVSKF	0.41 mM	(Nardo et al., 2020)
Rice	FNVPSRYGIY and WEDIGTIK	2.7 mg/mL 0.87 mg/mL	(Pinciroli et al., 2019)
P. palmata	AGGEY, IRLIIVLMPILMA, VYRT, and IKGHY	3.34 mM	(Aluko, 2019)
Rape seed protein	LY, GHS and RALP	0.97 mM	(He, Bu, et al., 2019)
ACE inhibitor peptides
Wheat gluten	LVS, LY, APSY, YQ, and RGGY	0.31, 0.60, 2.00, 1.47 and 1.48 mmol/L	(Liu, Zhang, et al., 2021)
Amaranth grains	AFEDGFEWVSKF and SFNLPILR	2.50 and 1.47 mM, respectively	(Nardo et al., 2020)
Ginkgo biloba	RADFY, TNLDWY, and RVFDGAV	1.93, 1.35, and 1.01 mM, respectively	(Ma et al., 2019)
Cottonseed	YRKISQL and FPAIGMK	46.7 μg/mL	(Gao et al., 2019)
Gingko biloba seed	TNLDWY, RVFDGAV, and RADFY	1.006 mM	(Ma et al., 2019)
Longan seed	ETSGMKPTEL, ISSMGILVCL	2.15 μM	(Nuchprapha et al., 2020)
Sesame seed	ISGAQPSLR, GHITVAR, and VVISAPSK	3.60 μM	(Wang et al., 2019)
Moringa oleifera leaf	IPPAYSK, LGF and ILVDR	0.29 mM	(Ma, Li, et al., 2021)
Moringa oleifera leaf	FFFPK, GLFF, and LLDPR	0.31 mM	(Ma, Li, et al., 2021)
Pearl Oyster	HLHT, GWA	458.06 μM	(Liu et al., 2019)

3.6. Wound healing

Fermented plant-based foods are emerging as a valuable source of bioactive peptides with therapeutic potential, particularly in wound healing. During fermentation, proteolytic enzymes from microbes hydrolyze plant proteins into short peptides, some of which exhibit antioxidant, anti-inflammatory, and antimicrobial activities all essential for efficient wound repair.

Studies have shown that peptides derived from fermented soy, mung bean, and rice bran possess free radical scavenging capacity and modulate inflammatory pathways, which can accelerate the wound healing process. For instance, Brucea javanica (L.) Merr. globulins were hydrolyzed with pepsin, then ultra-filtrated to collect small molecular peptides (≤3 kDa). The peptides were then analyzed by anti-proliferative assay, cell-cycle distribution, apoptosis assay, and in vitro wound-scratch assay. Finally, western blotting was conducted to elucidate the underlying anti-melanoma mechanism. The small molecular peptide from B. javanica significantly inhibited malignant melanoma cell proliferation with the IC₅₀ of 2.72 μg/mL for 72 h. Further analysis indicated that B. javanica peptides arrested cell cycle at the S and G2/M phases and induced apoptosis by upregulating p21, p53, Bax, caspase-3, and cleaved PARP while downregulating Bcl-2 expression. The inhibitory migration effects were also confirmed by wound-healing assay (Zhao et al., 2022).

Moreover, a study by Diao et al. isolated three bioactive peptides from mung bean protein hydrolysates (MBPH) using Sephadex G-15 chromatography. Among these, MBPH-3 demonstrated the most potent immunomodulatory activity, enhancing macrophage proliferation by 9.05% and elevating cytokine (IL-1β, IL, TNF-α) secretion while simultaneously suppressing LPS-induced cytokine release. Structural characterization revealed that MBPH-3 has a molecular mass of 903 Da and an amino acid sequence of Asn-Asn-Tyr-Gly-Pro-Thr-Met (Diao et al., 2020). In a subsequent investigation, Diao et al. (2022) examined the effects of mung bean protein hydrolysate (MBPH) on LPS-induced macrophages. The treatment modified macrophage morphology, proliferation, and cell cycle progression, inducing a shift from the S to the G2 phase. Additionally, MBPH upregulated pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), yet it exerted an overall anti-inflammatory effect by attenuating LPS-induced inflammation, with peak cytokine secretion observed at 24 hours (P < 0.05). Notably, the MBPH-III fraction exhibited the strongest anti-inflammatory activity by inhibiting the NF-κB pathway through blockade of p65 and IκBα phosphorylation. The study further suggested that lower molecular weight fractions may serve as promising functional food ingredients for managing chronic inflammation. Expanding on these findings, Xu et al. (2025) investigated the therapeutic potential of mung bean peptides (MBPs) in ulcerative colitis (UC), given their established anti-inflammatory properties. Through structural analysis including amino acid composition, molecular weight, and peptide sequencing the researchers evaluated MBPs in a DSS-induced colitis mouse model. The results demonstrated that MBPs ameliorated colitis symptoms by improving colon length, reducing histological damage, and decreasing disease severity. Furthermore, MBPs restored intestinal barrier integrity by upregulating tight junction proteins (ZO-1, claudin-1) and modulating gut microbiota and cytokine balance. These findings highlight the potential of MBPs as an adjunct therapy for UC.

The potential of fermented plant-based peptides in wound healing is promising, yet major hurdles remain. Current research relies heavily on in vitro or animal models, which may not reflect human physiology. Variable fermentation conditions also yield inconsistent peptide composition and bioactivity, hindering reproducibility. Furthermore, their absorption, stability, and mechanisms of action are poorly understood. The next step is to validate efficacy and safety through clinical trials. Advanced omics technologies can elucidate molecular pathways, while optimizing fermentation and purification processes will enhance yield and consistency. Interdisciplinary collaboration is key to developing standardized, effective peptide-based therapeutics or functional foods for wound care, paving the way for innovative and sustainable interventions.

4. Challenges in harnessing BAPs for the nutraceutical and functional food industries

The efficiency of fermentation processes in generating BAPs is influenced by a complex interplay of microbial strains, substrate composition, and process parameters such as pH, temperature, and duration (Peres Fabbri et al., 2024; Siddiqui et al., 2023). While LAB and fungal species like Aspergillus oryzae are commonly employed due to their proteolytic capabilities, their enzymatic activity can vary significantly, resulting in inconsistent peptide yields (Peres Fabbri et al., 2024). For instance, plant-derived proteins often present structural challenges, including rigid cell walls and anti-nutritional compounds like phytates, which impede hydrolysis and necessitate costly pre-treatment steps such as thermal processing or enzymatic degradation (Ying et al., 2021). Scaling up these processes introduces further complications, as maintaining peptide specificity during large-scale fermentation remains a persistent bottleneck. Traditional purification methods, such as activity-guided fractionation, are labor-intensive and time-consuming, limiting their practicality for industrial applications (Chakrabarti et al., 2018).

In contrast, enzymatic hydrolysis offers greater predictability and control over peptide production. Enzyme selection and optimization are critical determinants of success here; for example, Alcalase has been shown to generate ACE-inhibitory peptides from rice bran more effectively than papain, highlighting the importance of enzyme-substrate compatibility (Ying et al., 2021). However, the structural complexity of plant proteins, such as globular configurations or cross-linked polypeptides, often hinders enzyme accessibility. Residual enzyme activity post-hydrolysis can also inadvertently alter peptide functionality, raising concerns about consistency. Emerging technologies, including pulsed electric fields (PEF) and high-pressure processing (HPP), aim to enhance proteolytic efficiency by modifying substrate structures, though their scalability and cost-effectiveness for industrial use require further validation (Peighambardoust et al., 2021; Rizwan et al., 2023)

A critical challenge for BAPs lies in ensuring their bioavailability. To exert systemic effects, peptides must resist degradation during gastrointestinal (GI) transit and remain intact until absorption. Many plant-derived peptides, however, are vulnerable to hydrolysis by digestive enzymes like pepsin and trypsin, leading to diminished bioactivity (Rizwan et al., 2023). For example, while dairy-derived ACE-inhibitory peptides such as Ile-Pro-Pro exhibit notable stability, their plant-based analogs often falter under GI conditions. Strategies to enhance stability, such as encapsulation in lipid-based carriers or structural modifications like cyclization, show promise but introduce production complexities (Peighambardoust et al., 2021; Peres Fabbri et al., 2024). While debittering techniques, such as enzymatic treatment with aminopeptidases or flavor masking using cyclodextrins, mitigate this issue, they risk compromising bioactivity or adding production costs (Peighambardoust et al., 2021; Ying et al., 2021). Furthermore, the functional performance of peptides in food matrices, such as emulsification or water-holding capacity, must be carefully balanced with bioactivity. Over-hydrolysis, for instance, can degrade amphiphilic structures, impairing emulsifying properties and limiting their application in products like plant-based meats or dairy alternatives (Peighambardoust et al., 2021).

Translating preclinical findings into human applications remains another critical barrier. Most evidence for plant-based BAPs derives from in vitro assays or animal studies, with limited clinical trials to validate efficacy and safety. For example, antioxidant peptides from fermented soybean (e.g., kinema) demonstrate potential in vitro, yet their in vivo effects and optimal dosages remain poorly characterized (Rizwan et al., 2023). Regulatory frameworks further complicate progress, as global disparities in health claim approvals and dosage standardization create uncertainty for manufacturers. This ambiguity discourages investment in large-scale production, particularly when competing with cheaper synthetic alternatives. Economic viability also hinges on optimizing production workflows. Sourcing high-quality plant substrates (e.g., non-GMO legumes) and refining fermentation cycles to minimize energy and time inputs are essential for cost reduction. Moreover, the underutilization of byproducts, such as defatted oilseed meals, represents a missed opportunity to integrate circular economy principles into peptide production.

In summary, advancing plant-based BAPs to mainstream adoption requires multidisciplinary innovation from strain engineering and process optimization to clinical validation and regulatory alignment to address the intertwined challenges of efficiency, stability, functionality, and scalability. Recent research has put forth novel strategies to effectively resolve specific issues associated with using BAPs in the functional foods and nutraceutical industry (Siciliano et al., 2021). These strategies have been offered to enhance the overall utilization and adoption of BAPs (Figure 2).

Fig 2.

Novel strategies to effectively resolve specific issues associated with using bioactive peptides in functional foods and the nutraceutical industry.

5. Factors affecting the bioavailability of bioactive peptides

To be deemed suitable for incorporation into functional foods, bioactive peptides from sources like fermented plant foods must undergo active absorption upon ingestion and successfully reach their target cells or organs to execute their biological effects. The observation of these peptides having low bioavailability, particularly when delivered orally, can be attributed to the hydrolytic activity of digestive enzymes in the saliva and gastrointestinal system (Amigo & Hernández-Ledesma, 2020). Additionally, subsequent enzymatic breakdown of bioactive peptides occurs following their absorption through the intestinal barrier, facilitated by peptidases in the bloodstream (Pei et al., 2022). As a result, scholarly investigations have primarily concentrated on identifying bioactive peptides from fermented foods that can evade the hydrolytic activity of these peptidases.

Alternatively, researchers have explored several methods to modify bioactive peptides to impede their inhibition during digestion and transport (Udenigwe et al., 2021). Artificially produced peptides provide the advantage of being customizable and have been engineered to exhibit many bioactivities, including antibacterial and anticancer properties (Bhat et al., 2022). Synthetic short peptides have been employed in developing strategies to inhibit biofilm formation by oral bacterial pathogens. Researchers have developed synthetic bioactive peptides that exhibit enhanced bioavailability and can evade gastrointestinal digestion (Grover et al., 2022). Researchers have successfully designed cyclic peptides that exhibit the capacity to overcome issues related to metabolic instability, aiming to improve the bioavailability of peptide therapies (Merz et al., 2024). As indicated by previous research, the bioavailability of chemically generated cyclic peptides can be further enhanced through N-alkylation (Fetse et al., 2023; Fowler & Kim, 2024). It is also possible to engineer synthetic bioactive peptides to minimize the likelihood of adverse effects upon consumption (Shwaiki et al., 2021). Therefore, the advancement of synthetic peptides mitigates the constraints linked to endogenous peptides derived from fermented foods, including limited bioavailability, weak cell permeability, and reduced stability (Abdildinova et al., 2021).

Maintaining biostability is of utmost importance for peptides from fermented plant foods to facilitate the manifestation of health-promoting effects following ingestion. Peptides that can evade hydrolysis by proteases in the gastrointestinal (GI) tract exhibit strong potential as viable options for advancing nutraceuticals and/or functional foods (Udenigwe et al., 2021). Additionally, peptides that undergo gastrointestinal digestion to produce shorter bioactive sequences can be utilized as pro-peptides and incorporated into functional foods (Xue et al., 2021). Using computational methods to analyze the hydrolytic capacity of peptides contributes to identifying those from fermented sources that exhibit resistance to gastrointestinal digestion (Guo et al., 2021). Online programs like BIOPEP (Ramos & Kempka, 2024) and ExPASy PeptideMass (Su et al., 2024) can be utilized for conducting in silico simulations of peptide hydrolysis with specific enzymes. The hydrolyzed peptide fragment sequences resulting from in-silico hydrolysis can be queried in bioactive peptide databases (Morena et al., 2024).

Peptidomics analysis methods, such as Peptigram, have been employed to visually represent the distribution of peptides in a fermented food, both pre- and post-gastrointestinal (GI) digestion, based on the peak intensities of detected peptides (Wei et al., 2022). The enhancement of peptide bioavailability from fermented plant foods can be achieved by altering the structure of endogenous bioactive peptides at their cleavage sites to inhibit hydrolysis (Udenigwe et al., 2021). Chemical modifications such as acylation (Jensen et al., 2022), disulfide bond formation, and cyclization can also be employed in such accomplishment (Oba et al., 2019). Using suitable carrier molecules can also potentially enhance the bioavailability of bioactive peptides in functional foods (Udenigwe et al., 2021). In peptide administration, chemically unreactive carriers, such as fiber-rich foods that exhibit relative inertness, have been identified as viable options. These carriers enable the absorption of bioactive peptides while preserving their native structure and function (Udenigwe et al., 2021). In contrast, complex-forming matrices, such as lipid-based carriers, can be utilized for a regulated distribution of bioactive peptides through hydrolysis by gastrointestinal enzymes during digestion (Sun & Udenigwe, 2020).

Peptide encapsulation has been identified as a key approach for facilitating the transport of bioactive peptides from fermented foods for intestinal absorption (Wang & Selomulya, 2020). Encapsulating the peptide offers protection from the modifying influences of the gastrointestinal system and facilitates the controlled release of the peptide in its whole structure, thereby enhancing its bioavailability (Udenigwe et al., 2021). Various carriers have been suggested for the oral administration of bioactive peptides, such as emulsions (including nanoemulsions, multiple emulsions, and microemulsions) (Perry & McClements, 2020), biopolymer gels, liposomes, and solid-lipid nanoparticles (Manzanares et al., 2019). Encapsulation can be achieved using natural inclusion complexes, such as chitosan-fabricated nanocarriers and nanoliposomes derived from soy lecithin. Additionally, methacrylate and alginate microgels have demonstrated the ability to enhance the bioavailability of bioactive peptides, making these techniques highly applicable for delivering peptides from fermented plant foods in the nutraceutical and functional food sectors (Udenigwe et al., 2021).

6. Conclusion

Based on the global significance of fermentation in health, traditional value, and nutritional value, there is a constant significant interest in closely studying and improving the quality of fermented plant-based foods and, in our instance, solid fermented. BAPs are a highly valuable category of functional molecules with a wide range of health-promoting effects. Various starter microorganisms are utilized to produce FPFs and release various chemicals. BAPs have the potential to exhibit significant bioactivity while minimizing adverse effects, making them viable substitutes for synthetic molecules in the formulation of nutraceuticals and functional food products. Several peptides have been found to exhibit mutagenicity, toxicity, or allergenicity, and it is imperative to exclude these peptides during the manufacturing of functional foods. The functional food sector has various challenges in the exploitation of bioactive peptides. However, these challenges can be effectively addressed through several strategies. These strategies include enhanced in silico approaches, peptidomics, peptide debittering, and peptide encapsulation. Future researchers can employ such techniques and/or devise innovative approaches to improve peptide bio-accessibility and optimize organoleptic qualities to advance the field of functional food products and nutraceutical development. Besides, future studies should explore how certain microbial strains that are more effective in BAP production and if specific fermentation substrates lead to broader peptide diversity. Research should be done to assess whether smaller peptides exhibit higher bioavailability or potency.

CRediT authorship contribution statement

Benjamin Bonsu Bruce: Writing – review & editing, Writing – original draft, Software, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Isaac Duah Boateng: Writing-review & editing, Methodology, Formal analysis, Visualization, Supervision. Charllote Boateng: Writing – review & editing, Visualization, Supervision.

Funding

No Funding

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.