Hypertension is a prevalent and common chronic disease that severely endangers human life and health. Globally, approximately 3.5 billion adults present suboptimal blood pressure levels, with a notable trend of younger onset [1]. The blood pressure regulatory system comprises the autonomic nervous system, vascular tone regulation system, renin-angiotensin-aldosterone system (RAAS), renal system and other functional modules. Among these, the RAAS exerts a pivotal role in arterial blood pressure regulation and extracellular fluid homeostasis maintenance [2].

Angiotensin-converting enzyme (ACE) serves as a core component of the RAAS. Inhibition of ACE activity reduces the biosynthesis of angiotensin II (Ang II), thereby inducing vasodilation and hypotensive effects. Currently, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers constitute the predominant first-line antihypertensive pharmacotherapies [3-4]. Although these clinical agents exhibit satisfactory tolerability, nearly 20% of patients discontinue ACEI treatment due to adverse drug reactions such as chronic cough [5]. Accordingly, it is imperative to explore safer and more efficient hypotensive strategies and develop novel ACEIs characterized by superior efficacy, minimal side effects and high biosafety.

Accumulated studies have demonstrated that bioactive peptides liberated from food proteins possess multiple physiological functions, including antioxidant, antihypertensive, antibacterial, antithrombotic and immunomodulatory activities [6-7]. Angiotensin-converting enzyme inhibitory peptides (ACEIPs) are distinguished by high biological activity, favorable biosafety and efficient in vivo metabolic characteristics, rendering them increasingly prominent in the research and development of functional foods [8]. ACEIPs and their extracts can be efficiently prepared from dietary raw materials such as milk, meat and rice via enzymatic hydrolysis and microbial fermentation. These bioactive compounds exhibit potent ACE inhibitory capacity and prominent hypotensive properties, demonstrating broad application prospects in the food industry [9-11]. Nevertheless, the production of animal-derived proteins entails excessive energy consumption and substantial greenhouse gas emissions, which conflict with contemporary environmental sustainability concepts [12]. Plant-based raw materials, particularly cereal crops represented by rice, have garnered escalating research attention for ACEIP preparation by virtue of abundant raw material reserves and eco-friendly production advantages [7,13-14]. This review systematically summarizes the regulatory mechanisms of the blood pressure homeostasis system, the hypotensive pathways of ACEIPs, as well as their structural and functional characteristics. Particular emphasis is placed on elaborating the research advances in the preparation, separation and purification of rice-derived ACEIPs through enzymatic hydrolysis and fermentation technologies. This work aims to provide theoretical foundations for the industrial development of food-originated ACEIP products and the high-value extension of the rice industrial chain.

一.Blood Pressure Regulation and Hypotensive Mechanisms

1.Regulatory Mechanisms of the Blood Pressure System

The inhibitory efficacy against ACE is primarily associated with two pivotal blood pressure regulatory axes: the renin-angiotensin system (RAS) and nitric oxide system (NOS). As illustrated in Figure 1, renin, a proteolytic enzyme synthesized by juxtaglomerular cells, catalyzes the conversion of angiotensinogen into angiotensin I (Ang I). ACE further mediates the transformation of Ang I into Ang II, which subsequently activates angiotensin II type 1 receptors (AT1R) and triggers a cascade of pathological responses including vasoconstriction, tissue fibrosis, inflammatory infiltration and reactive oxygen species (ROS) overproduction. Meanwhile, moderate levels of Ang II bind to angiotensin II type 2 receptors (AT2R) to counterbalance AT1R-mediated biological effects, thereby sustaining the physiological homeostasis of the RAS [15].

Zinc metalloprotease ACE2 is capable of degrading Ang II to generate Ang-(1-7), or directly converting Ang I into Ang-(1-9). The intermediate product Ang-(1-9) can be further hydrolyzed by ACE to produce Ang-(1-7). Functionally opposite to Ang II, Ang-(1-7) specifically couples with corresponding G-protein-coupled receptors to exert vasodilatory, anti-inflammatory and anti-fibrotic bioactivities, and is ultimately degraded by ACE into inactive Ang-(1-5) fragments [16]. Hence, ACE occupies a more dominant regulatory position than ACE2 within the RAS cascade. Both aminopeptidase A (AP-A) and aminopeptidase N (AP-N) catalyze the biotransformation of Ang II into Ang IV. Additionally, Ang IV binds to insulin-regulated aminopeptidase receptors (IRAP), resulting in adverse physiological outcomes such as vasoconstriction, inflammatory responses and ROS accumulation [17].

2.Structural Characteristics of ACEIPs

The physiological functions of ACEIPs are intrinsically correlated with their polypeptide structures, with key determinants including molecular weight, amino acid composition and sequence arrangement. The bioactivity of ACE inhibitory peptides is closely related to molecular mass. Multiple studies have verified that short-chain peptides containing 2 to 12 amino acid residues (with molecular weights generally below 3000 Da) can optimally bind to the active sites of ACE [18-19]. In most ACEIP sequences, the last three amino acid residues at the C-terminus are hydrophobic amino acids, which bind to the terminal catalytic sites of ACE to achieve targeted enzyme inhibition.

ACEIPs with proline (Pro) at the C-terminus have been validated to possess enhanced inhibitory potency and superior resistance to digestive enzyme degradation [20-21]. Hydroxyproline (Hyp) plays a critical role in the molecular interaction with the ACE active pocket, and its presence at the penultimate position of the C-terminus significantly enhances ACE inhibitory activity [22-23]. For tetrapeptide ACEIPs, specific residue combinations confer potent inhibitory effects: tyrosine (Tyr) or cysteine (Cys) at the first position, histidine (His), tryptophan (Trp) or methionine (Met) at the second position, isoleucine (Ile), leucine (Leu), valine (Val) or methionine (Met) at the third position, and tryptophan (Trp) at the fourth position [24-25]. Molecular docking analysis further clarifies the binding modes of ACEIPs. As depicted in Figure 2, the tripeptide Tyr-Ser-Lys (YSK) exerts ACE inhibitory effects mainly via hydrogen bond formation within the ACE active pocket [26].

Current research also indicates that hydrophobic amino acids at the N-terminus endow polypeptides with strong ACE inhibitory capacity, while basic amino acid residues at the N-terminus can strengthen molecular affinity to ACE and further elevate antihypertensive bioactivity [18-19,27]. Beyond the 20 canonical amino acids, non-canonical amino acids also modulate ACEIP bioactivity. For instance, citrulline (Cit) with neutral net charge increases protein hydrophobicity upon accumulation; ornithine (Orn), a typical basic amino acid, can enhance ACEIP activity when located at the N-terminus. Both non-canonical amino acids exhibit antioxidant and vascular-protective properties, which may assist in alleviating adverse physiological side effects [28-30].

3.Preparation Methods of Rice-Derived ACEIPs

Major fabrication technologies for bioactive peptides include solvent extraction, enzymatic hydrolysis, microbial fermentation, chemical synthesis and genetic engineering recombination [31]. Solvent extraction is characterized by simple principles and convenient operational procedures; in vitro synthetic approaches such as chemical synthesis and recombinant genetic engineering offer distinct advantages of short production cycles and high yield, effectively compensating for the limitations of natural peptide acquisition [32]. In contrast, enzymatic hydrolysis and microbial fermentation have evolved as mature industrial preparation methods due to high biosafety, robust biological activity and specific catalytic specificity. With the rapid advancement of biotechnology, innovative strategies for natural peptide production continue to emerge. At present, enzymatic hydrolysis and microbial fermentation represent the mainstream technical routes for ACEIP production using food-derived raw materials.

二. Preparation of Rice-Derived ACEIPs via Enzymatic Hydrolysis

1. Utilization of Different Rice Fractions

Rice contains a relatively low protein content (approximately 8%), whereas the nutritional value and health-promoting properties of rice proteins have been widely recognized [33]. Native rice proteins exhibit poor solubility and digestibility under neutral conditions, and enzymatic modification can effectively improve their functional and biological properties. Proteins isolated from rice can be hydrolyzed into abundant bioactive peptides, which exert dose-dependent ACE inhibitory effects at appropriate concentrations [34-35]. As summarized in Table 1, rice protein hydrolysates prepared via hydrolysis with multiple commercial enzyme preparations display efficient in vivo and in vitro hypotensive activities. Several typical rice-derived ACEIPs have been successfully identified, including Ile-His-Arg-Phe (IHRF), Val-Asn-Pro (VNP) and Val-Trp-Pro (VWP) [36-37].

Preliminary separation of rice protein hydrolysates can be achieved through ultrafiltration and DA201 macroporous adsorption resin, followed by two-step reversed-phase high-performance liquid chromatography (RP-HPLC) purification to obtain two high-purity tripeptides with prominent ACE inhibitory activity [37]. Six novel ACE inhibitory peptides have been separately isolated from red yeast rice and traditional Korean rice wine in previous studies [38-39]. Moreover, oral administration of fermented brown rice aqueous extracts and rice residue protein hydrolysates containing peptide components yields marked hypotensive outcomes in spontaneously hypertensive rats (SHRs) [40].

Proteins extracted from rice processing by-products present favorable biological characteristics (Table 1). Rice bran, rice residue and distillers’ grains are cost-effective and sustainable raw material sources for ACEIP production. Unhydrolyzed rice bran proteins demonstrate weaker ACE inhibitory activity compared with their enzymatic hydrolysates. Commercial protease-treated rice bran protein hydrolysates feature low relative molecular weight and potent in vitro ACE inhibitory activity. Enzymatically modified rice bran proteins can be developed as high-value functional food ingredients with superior bioavailability and absorption efficiency [51].

Novel bioactive peptides are continuously discovered from rice by-products. For example, a novel ACE inhibitory peptide with the sequences of Ile-Thr-Leu (ITL) or Leu-Thr-Ile (LTI) was purified from alkaline protease-hydrolyzed rice bran protein via size-exclusion chromatography and RP-HPLC, whose in vitro ACE inhibitory potency was comparable to that of enalapril maleate [47,52]. Multiple dipeptides and tripeptides with validated in vivo and in vitro ACE inhibitory effects have been identified in rice bran enzymatic hydrolysates [53-54]. Rice bran protein hydrolysates exhibit efficient ACE suppression capacity, with pharmacological effects analogous to the classic hypotensive drug captopril [55]. Additionally, protein hydrolysates derived from brown rice, refined rice protein and germinated brown rice also possess inherent ACE inhibitory potential [56-59].

2.Application of Enzymatic Preparations

As listed in Table 1, proteases including alkaline protease, trypsin, neutral protease and pepsin display unique cleavage sites and optimal reaction conditions, contributing to differential hypotensive performance in ACEIP preparation. Alkaline protease is the most widely adopted and high-efficiency protease in current research, which is closely associated with the poor solubility of rice proteins under acidic and neutral environments. A comparative study on the enzymatic hydrolysis efficiency of rice bran protein concentrate and soybean protein was conducted using alkaline protease, papain and commercial compound enzymes containing trypsin, thymoprotease and aminopeptidase. The results confirmed that alkaline protease possesses superior hydrolytic capacity and ACE inhibitory modification efficiency [60].

Enzymatically treated rice bran serves as an excellent natural source of bioactive peptides, showing promising therapeutic potential for hypertension and related metabolic disorders. Beyond ACE inhibitory activity, rice protein hydrolysates obtained via enzymatic degradation exhibit strong free radical scavenging capacity and reducing power. These multifunctional hydrolysates can be applied as functional food additives in nutritional foods and beverages, delivering comprehensive health benefits and satisfactory sensory quality [56-59].

三. Separation and Identification Technologies for ACEIPs

The conventional technical workflow for ACEIP separation and identification consists of three core steps: separation of rice-derived crude polypeptides using membrane separation technology, gel filtration chromatography and RP-HPLC; amino acid sequence identification via mass spectrometry; and determination of interaction sites and binding patterns through molecular docking simulation, which collectively assist the targeted separation and structural characterization of ACEIPs [26,37,47].

Innovative monitoring technologies have also been integrated into the enzymatic hydrolysis process. For instance, in-situ near-infrared spectroscopy combined with chemometric algorithms enables real-time detection of ACE inhibitory activity during dual-enzyme hydrolysis of rice-derived substrates. This integrated monitoring system can precisely regulate the hydrolysis termination point and adaptive transition parameters, thereby improving overall enzymatic hydrolysis efficiency [42]. Surface plasmon resonance and other biophysical technologies can simulate enzymatic hydrolysis and fermentation conditions to screen potential bioactive peptides, facilitate structural characterization and mechanism elucidation, and provide theoretical guidance for the functional prediction of ACE inhibitory peptides.

In silico screening strategies are increasingly applied in ACEIP research. By comparing acquired peptide sequences with published polypeptide databases from plant, animal and other food sources, bioinformatics databases such as BIOPEP and computer-aided matching tools can rapidly screen candidate bioactive peptides, whose actual biological activity is further verified through in vitro experiments to explore novel ACE inhibitory components [82-83]. Furthermore, systematic assessment and predictive analysis of the physicochemical properties, primary structures, toxicological risks and allergenicity of most ACE inhibitory peptides can be performed, so as to comprehensively guarantee the safety of final functional food products [84]. The combined application of these advanced separation and identification technologies greatly promotes the basic research and industrial development of rice-derived hypotensive functional foods and other bioactive food products.

四. Research Prospects and Limitations of Rice-Derived ACEIPs

The production of ACEIPs from rice and its processing by-products via enzymatic hydrolysis, microbial fermentation or combined biotechnological strategies presents enormous development potential. Consumers have gradually recognized the unique functional advantages and nutritional value of rice-derived functional products. Nevertheless, compared with animal-derived and other plant-derived bioactive peptides, research on rice-based ACEIPs prepared by enzymatic hydrolysis and fermentation remains relatively limited, leaving substantial room for in-depth exploration and industrial application.

The structure-activity relationship of ACEIPs and their functional regulatory mechanisms require further systematic investigation. In particular, in vivo metabolic pathways and clinical evidence of fermented rice-derived ACEIPs are still insufficient. Future research on the bioactivity of ACEIPs is expected to rely on multi-omics technologies including genomics and metabolomics to clarify their biosynthesis mechanisms and structural contributions to physiological functions. Transcriptomics and other molecular biological approaches, combined with computational simulation software, can be utilized to analyze the interactive relationships among fermentative microorganisms, optimize the targeted biosynthesis of rice-derived bioactive peptides, and elucidate their intracellular metabolism and transmembrane transport mechanisms.

Further in-depth research is urgently required to enhance peptide production efficiency and oral bioavailability, evaluate the in vivo bioaccessibility and long-term hypotensive efficacy of rice-derived ACEIPs. Collectively, ongoing mechanistic and applied research will provide solid theoretical and technical support for the innovative development and clinical auxiliary application of health care products and adjuvant antihypertensive agents based on rice bioactive peptides.

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Research Progress on Angiotensin-Converting Enzyme Inhibitory Peptides Derived from Rice