Animal collagen as a source of antihypertensive bioactive peptides: production technologies, structural characteristics, and molecular mechanisms

Abstract

Hypertension affects approximately 1.4 billion adults globally, yet nearly 80% of hypertensive individuals remain inadequately controlled, underscoring the urgent need for safe, food-based interventions. Collagen-derived bioactive peptides from animal sources represent promising functional food ingredients for blood pressure management through controlled enzymatic hydrolysis. This review integrates evidence from source characteristics through clinical validation. A critical synthesis of 47 characterized peptides across bovine, porcine, poultry, and marine sources suggests that enzymatic processing parameters, rather than source origin per se, are key determinants of peptide bioactivity, with hydrolysis conditions critically influencing peptide size distribution, sequence diversity, and ACE inhibitory potency. Multiple complementary mechanisms extending beyond angiotensin-converting enzyme inhibition—including antioxidant activity, endothelial function restoration, and renin-angiotensin system modulation—operate synergistically, contributing to blood pressure reduction. Clinical evidence from randomized controlled trials and meta-analyses confirms significant antihypertensive efficacy in humans with favourable safety profiles. Quality standardization encompassing structure-activity characterization and functional biomarkers remains a key bottleneck for functional food applications. This review bridges agricultural animal production and food science by establishing a comprehensive framework linking collagen source selection, processing technology, peptide structure, and clinical outcomes—providing actionable guidance for developing evidence-based antihypertensive functional foods.

Keywords

Collagen / Bioactive peptides / Antihypertensive / ACE inhibition / Functional foods

References

[1] WHO. Global report on hypertension: the race against a silent killer. World Health Organization; 2023.

[2] Kario K, Okura A, Hoshide S, Mogi M. The WHO Global report 2023 on hypertension warning the emerging hypertension burden in globe and its treatment strategy. Hypertens Res, 2024, 4751099102.

[3] Coca A. 2026 Latin American consensus for the management of patients with hypertension and cardio-renal and metabolic disturbances: endorsed by the Latin American Society of Hypertension, the Iberoamerican Hypertension League, and the World Hypertension League. J Hypertens, 2026, 446885910.

[4] Qu Z, Wang X. The regulatory role of the renin-angiotensin system in the tumor microenvironment and immunotherapy of hepatocellular carcinoma. J Renin Angiotensin Aldosterone Syst, 2026, 27: 14703203251409639.

[5] Wu Y, Deng S, Wei W, He Y, He Y, Hong G, et al. Oral collagen-based supplement as a bioactive component in functional foods. Collagen Leather, 2025, 7115.

[6] Sangsawad P, Chumee S, Laosam P, Roytrakul S, Katemala S, Sutheerawattananonda M. Pilot-scale production of sericin-derived oligopeptides (SDOs) from yellow silk cocoons: peptide characterization and specifications. Foods, 2025, 143500.

[7] Shah P, et al. From traditional to modern medicine: the role of herbs and phytoconstituents in pharmaceuticals, nutraceuticals, and cosmetics. In: Formulating Pharma-, Nutra-, and cosmeceutical products from herbal substances: dosage forms and delivery systems. 2025. pp. 3–73.

[8] Han R, et al. Crucian carp-derived ACE-inhibitory peptides with in vivo antihypertensive activity: insights into bioactivity, mechanism, and safety. Molecules, 2025, 30132812.

[9] Li J, et al. Two antihypertensive and antioxidant peptides derived from Alaska pollack (Theragra chalcograma) skin: in silico, in vitro, and in vivo investigation. J Agric Food Chem, 2025, 7316993245.

[10] Tarnutzer K, Siva Sankar D, Dengjel J, Ewald CY. Collagen constitutes about 12% in females and 17% in males of the total protein in mice. Sci Rep, 2023, 1314490.

[11] Shahrajabian MH, Sun W. Mechanism of action of collagen and epidermal growth factor: a review on theory and research methods. Mini Rev Med Chem, 2024, 24445377.

[12] Luo J, Yang X, Cao Y, Li G, Meng Y, Li C. Structural characterization and in vitro immunogenicity evaluation of amphibian-derived collagen type II from the cartilage of Chinese Giant Salamander (Andrias davidianus). J Biomater Sci Polym Ed, 2020, 3115194160.

[13] van Huizen NA, Ijzermans JN, Burgers PC, Luider TM. Collagen analysis with mass spectrometry. Mass Spectrom Rev, 2020, 39430935.

[14] Islam J, Solval KEM. Recent advancements in marine collagen: exploring new sources, processing approaches, and nutritional applications. Mar Drugs, 2025, 23: 190.

[15] Cheng JH, Zhang XY, Wang Z, Zhang X, Liu SC, Song XY, et al. Potential of thermolysin-like protease A69 in preparation of bovine collagen peptides with moisture-retention ability and antioxidative activity. Mar Drugs, 2021, 1912676.

[16] Matinong AME, Chisti Y, Pickering KL, Haverkamp RG. Collagen extraction from animal skin. Biology, 2022, 116905.

[17] Harris M, Potgieter J, Ishfaq K, Shahzad M. Developments for collagen hydrolysate in biological, biochemical, and biomedical domains: a comprehensive review. Materials, 2021, 14112806.

[18] Borrajo P, Pateiro M, Barba FJ, Mora L, Franco D, Toldrá F, et al. Antioxidant and antimicrobial activity of peptides extracted from meat by-products: a review. Food Anal Methods, 2019, 12: 2401-15.

[19] Permadi SN, Ujilestari T, Hakim L, Jambang N, Yuliatmo R, Febrisiantosa A, et al. Characteristics and applications of collagen from the animal by-product as a potential source for food ingredients. Rev Agric Sci, 2024, 12: 327-46.

[20] López-Martínez MI, Toldrá F, Mora L. Sequential enzymatic hydrolysis and ultrasound pretreatment of pork liver for the generation of bioactive and taste-related hydrolyzates. J Agric Food Chem, 2024, 722815693703.

[21] Salim NV, Madhan B, Glattauer V, Ramshaw JAM. Comprehensive review on collagen extraction from food by-products and waste as a value-added material. Int J Biol Macromol, 2024, 278: 134374.

[22] Segarra S, de la Torre C, Bech-Serra JJ, Cucurull B, Marazuela-Duque A, Vaquero A, et al. The discovery, characterization, and quantification of bioactive peptides contained in palbio porcine intestinal mucosa hydrolysate products. Int J Mol Sci, 2025, 26: 6656.

[23] López-Pedrouso M, Zaky AA, Lorenzo JM, Camiña M, Franco D. A review on bioactive peptides derived from meat and by-products: extraction methods, biological activities, applications and limitations. Meat Sci, 2023.

[24] Cao C, Xiao Z, Ge C, Wu Y. Animal by-products collagen and derived peptide, as important components of innovative sustainable food systems: a comprehensive review. Crit Rev Food Sci Nutr, 2022, 6231870327.

[25] Amiri A, Sharifian P, Soltanizadeh N. Application of ultrasound treatment for improving the physicochemical, functional and rheological properties of myofibrillar proteins. Int J Biol Macromol, 2018, 111: 139-47.

[26] Jogi N, Yathisha UG, Bhat I, Mamatha BS. Antihypertensive activity of orally consumed ACE-I inhibitory peptides. Crit Rev Food Sci Nutr, 2022, 6232898699.

[27] Laosam P, Luasiri P, Nakharuthai C, Boonanuntanasarn S, Suwanangul S, Sarnthima R. Enzymatic hydrolysis of duck blood protein produces stable bioactive peptides: pilot-scale production, identification, and stability during gastrointestinal and plasma digestion. Int J Biol Macromol, 2024.

[28] Pillai NS, Khan SA, Mehrotra N, Jadhav K. A comprehensive review on the role of collagen in health and disease. Biosci Biotechnol Res Asia, 2024, 214132947.

[29] Qin D, Bo W, Zheng X, Hao YH, Li B, Zheng J, et al. DFBP: a comprehensive database of food-derived bioactive peptides for peptidomics research. Bioinformatics, 2022, 3812327580.

[30] Jang A, Lee M. Purification and identification of angiotensin converting enzyme inhibitory peptides from beef hydrolysates. Meat Sci, 2005, 69465361.

[31] Auwal SM, Ghanisma SBM, Saari N. Improved systolic blood pressure (SBP)-lowering effect of stone fish-derived angiotensin-I converting enzyme (ACE)-inhibitory peptide entrapped in chitosan-coated alginate nanocomposites. Food Biosci, 2024, 60: 104349.

[32] Cao S, Wang Y, Hao Y, Zhang W, Zhou G. Antihypertensive effects in vitro and in vivo of novel angiotensin-converting enzyme inhibitory peptides from bovine bone gelatin hydrolysate. J Agric Food Chem, 2020, 68375968.

[33] Acharya KR, Gregory KS, Sturrock ED. Advances in the structural basis for angiotensin-1 converting enzyme (ACE) inhibitors. Biosci Rep, 2024, 448BSR20240130.

[34] Xiang H, Huang H, Shao Y, Hao S, Li L, Wei Y, et al. Angiotensin-I-converting enzyme inhibitory peptides from eel (Anguilla japonica) bone collagen: preparation, identification, molecular docking, and protective function on HUVECs. Front Nutr, 2024, 11: 1462656.

[35] Yu Z, Wu S, Zhao W, Mi G, Ding L, Li J, et al. Identification of novel angiotensin I-converting enzyme inhibitory peptide from collagen hydrolysates and its molecular inhibitory mechanism. Int J Food Sci Technol, 2020, 559314552.

[36] Hu YD, Xi QH, Kong J, Zhao YQ, Chi CF, Wang B. Angiotensin-I-converting enzyme (ACE)-inhibitory peptides from the collagens of monkfish (Lophius litulon) swim bladders: isolation, characterization, molecular docking analysis and activity evaluation. Mar Drugs, 2023, 2110516.

[37] Zhou F, Li D, Hou Y, Cong Z, Li K, Gu X, et al. Exploration of hypoglycemic peptides from porcine collagen based on network pharmacology and molecular docking. PLoS ONE, 2024, 193e0298674.

[38] Camargo LL, Rios FJ, Montezano AC, Touyz RM. Reactive oxygen species in hypertension. Nat Rev Cardiol, 2025, 2212037.

[39] Purba RAP, Laosam P, Pongsamai N, Sangsawad P. Comparative evaluation of takhrai (Cymbopogon citratus) leaf extracts with commercial antioxidants for oxidative stress mitigation in ruminants under heat stress. Vet Sci, 2025, 125432.

[40] Lamb FS, Choi H, Miller MR, Stark RJ. TNFα and reactive oxygen signaling in vascular smooth muscle cells in hypertension and atherosclerosis. Am J Hypertens, 2020, 331090213.

[41] Badran A, Nasser SA, Mesmar J, El-Yazbi AF, Bitto A, Fardoun MM, et al. Reactive oxygen species: modulators of phenotypic switch of vascular smooth muscle cells. Int J Mol Sci, 2020, 21228764.

[42] Tahergorabi R, Abdollahi M. Marine bioactives. In: Food bioactives health. 2021. pp. 195–235.

[43] Fan H, Liao W, Spaans F, Pasha M, Davidge ST, Wu J. Chicken muscle hydrolysate reduces blood pressure in spontaneously hypertensive rats, upregulates ACE2, and ameliorates vascular inflammation, fibrosis, and oxidative stress. J Food Sci, 2022, 8731292305.

[44] Tawalbeh D, Kha’sim MI, Mhd Sarbon N, Sarbon NM. Techno-functional and bioactivity properties of collagen hydrolysate and peptide: a review. Food Rev Int, 2025.

[45] Okagu IU, Ezeorba TP, Aham EC, Aguchem RN, Nechi RN. Recent findings on the cellular and molecular mechanisms of action of novel food-derived antihypertensive peptides. Food Chem Mol Sci, 2022, 4: 100078.

[46] Li Z, He H, Liu J, Gu H, Fu C, Zeb A, et al. Preparation and vasodilation mechanism of angiotensin-I-converting enzyme inhibitory peptide from Ulva prolifera protein. Mar Drugs, 2024, 229398.

[47] Knežević D, Ćurko-Cofek B, Batinac T, Laškarin G, Rakić M, Šoštarič M, et al. Endothelial dysfunction in patients undergoing cardiac surgery: a narrative review and clinical implications. J Cardiovasc Dev Dis, 2023, 105213.

[48] Kostov K. The causal relationship between endothelin-1 and hypertension: focusing on endothelial dysfunction, arterial stiffness, vascular remodeling, and blood pressure regulation. Life, 2021, 119986.

[49] Fernández-Sarmiento J, Salazar-Peláez LM, Carcillo JA. The endothelial glycocalyx: a fundamental determinant of vascular permeability in sepsis. Pediatr Crit Care Med, 2020, 215e291300.

[50] Yi W, Chen F, Zhang H, Tang P, Yuan M, Wen J, et al. Role of angiotensin II in aging. Front Aging Neurosci, 2022, 14: 1002138.

[51] Sansоè G, Aragno M, Wong F. Pathways of hepatic and renal damage through non-classical activation of the renin-angiotensin system in chronic liver disease. Liver Int, 2020, 4011831.

[52] Heres A, Mora L, Toldrá F. Bioactive and sensory di- and tripeptides generated during dry-curing of pork meat. Int J Mol Sci, 2023, 2421574.

[53] Olalere OA, Yap PG, Gan CY. Comprehensive review on some food-derived bioactive peptides with anti-hypertension therapeutic potential for angiotensin-converting enzyme (ACE) inhibition. J Proteins Proteom, 2023, 14212961.

[54] Daroit DJ, Brandelli A. In vivo bioactivities of food protein-derived peptides: a current review. Curr Opin Food Sci, 2021, 39: 120-9.

[55] Chi Y, Liu X, Chai J. A narrative review of changes in microvascular permeability after burn. Ann Transl Med, 2021, 98719.

[56] Bekassy Z, Lopatko Fagerström I, Bader M, Karpman D. Crosstalk between the renin-angiotensin, complement and kallikrein-kinin systems in inflammation. Nat Rev Immunol, 2022, 22741128.

[57] Fu Y, Young JF, Løkke MM, Lametsch R, Aluko RE, Therkildsen M. Revalorisation of bovine collagen as a potential precursor of angiotensin I-converting enzyme (ACE) inhibitory peptides based on in silico and in vitro protein digestions. J Funct Foods, 2016, 24: 196-206.

[58] Pearman NA, Morris GA, Smith AM. Angiotensin-converting enzyme (ACE)-inhibitor activity of novel peptides derived from porcine liver and placenta. Molecules, 2025, 30: 754.

[59] Lee SY, Hur SJ. Purification of novel angiotensin converting enzyme inhibitory peptides from beef myofibrillar proteins and analysis of their effect in spontaneously hypertensive rat model. Biomed Pharmacother, 2019, 116: 109046.

[60] Li B, Chen F, Wang X, Ji B, Wu Y. Isolation and identification of antioxidative peptides from porcine collagen hydrolysate by consecutive chromatography and electrospray ionization-mass spectrometry. Food Chem, 2007, 1024113543.

[61] González-Noriega JA, Valenzuela-Melendres M, Hernández-Mendoza A, Astiazarán-García H, Islava-Lagarda T, Tortoledo-Ortiz O, et al. Angiotensin converting enzyme inhibitory hydrolysate and peptide fractions from chicken skin collagen, as modulators of lipid accumulation in adipocytes 3 T3-L1, after in vitro gastrointestinal digestion. Food Chem, 2024, 460: 140551.

[62] Sarbon N, Howell N, Wan Ahmad WAN. Angiotensin-I converting enzyme (ACE) inhibitory peptides from chicken skin gelatin hydrolysate and its antihypertensive effect in spontaneously hypertensive rats. Int Food Res J, 2019, 26: 903-11

[63] Winarti A, Rahmawati F, Fitriyanto N, Jamhari J, Erwanto Y. Hydrolyzation of duck meat protein using Bacillus cereus TD5B protease, pepsin, trypsin and their potency as an angiotensin converting enzyme inhibitor. J Indonesian Trop Anim Agric, 2019.

[64] Laosam P. Thermally induced protein modifications in mealworm: gastrointestinal digestibility and derived bioactive peptides with antioxidants and ACE/DPP-IV inhibitory activities. Food Res Int, 2025.

[65] Fu Y, Young JF, Dalsgaard TK, Therkildsen M. Separation of angiotensin I-converting enzyme inhibitory peptides from bovine connective tissue and their stability towards temperature, pH and digestive enzymes. Int J Food Sci Technol, 2015, 505123443.

[66] Taga Y, Hayashida O, Ashour A, Amen Y, Kusubata M, Ogawa-Goto K, et al. Characterization of angiotensin-converting enzyme inhibitory activity of X-Hyp-Gly-type tripeptides: importance of collagen-specific prolyl hydroxylation. J Agric Food Chem, 2018, 6633873743.

[67] Tchekalarova J, Krushovlieva D, Ivanova P, Kortenska L. Spontaneously hypertensive rats vs. Wistar Kyoto and Wistar rats: an assessment of anxiety, motor activity, memory performance, and seizure susceptibility. Physiol Behav, 2023, 269: 114268.

[68] Zhang Y, Kouguchi T, Shimizu M, Ohmori T, Takahata Y, Morimatsu F. Chicken collagen hydrolysate protects rats from hypertension and cardiovascular damage. J Med Food, 2010, 132399405.

[69] Faria M, da Costa EL, Gontijo JA, Netto FM. Evaluation of the hypotensive potential of bovine and porcine collagen hydrolysates. J Med Food, 2008, 1135607.

[70] Gao X, Bu F, Yi D, Liu H, Hou Z, Zhang C, et al. Molecular docking and antihypertensive effects of a novel angiotensin-I converting enzyme inhibitory peptide from yak bone. Front Nutr, 2022, 9: 993744.

[71] Saiga A, Tanabe S, Nishimura T. Angiotensin I-converting enzyme-inhibitory peptides obtained from chicken collagen hydrolysate. J Agric Food Chem, 2008, 5620958691.

[72] Jalili Z, Jalili F, Moradi S, Bagheri R, Moosavian SP, Naeini F, et al. Effects of collagen peptide supplementation on cardiovascular markers: a systematic review and meta-analysis of randomised, placebo-controlled trials. Br J Nutr, 2023, 129577994.

[73] Kouguchi T, Ohmori T, Shimizu M, Takahata Y, Maeyama Y, Suzuki T, et al. Effects of a chicken collagen hydrolysate on the circulation system in subjects with mild hypertension or high-normal blood pressure. Biosci Biotechnol Biochem, 2013, 7746916.

[74] Ichimura T, Yamanaka A, Otsuka T, Yamashita E, Maruyama S. Antihypertensive effect of enzymatic hydrolysate of collagen and Gly-Pro in spontaneously hypertensive rats. Biosci Biotechnol Biochem, 2009.

[75] Zhu CF, Li GZ, Peng HB, Li Y, Zhang F, Chen Y. Therapeutic effects of marine collagen peptides on Chinese patients with type 2 diabetes mellitus and primary hypertension. Am J Med Sci, 2010, 34053606.

[76] Tak YJ, Kim YJ, Lee JG, Yi YH, Cho YH, Kang GH. Effect of oral ingestion of low-molecular collagen peptides derived from skate (Raja Kenojei) skin on body fat in overweight adults: a randomized, double-blind, placebo-controlled trial. Mar Drugs, 2019.

[77] Tomosugi N, Yamamoto S, Takeuchi M, Yonekura H, Ishigaki Y, Numata N, et al. Effect of collagen tripeptide on atherosclerosis in healthy humans. J Atheroscler Thromb, 2017, 2455308.

[78] Laosam P, et al. Molecular structures and in vitro bioactivities of enzymatically produced porcine placenta peptides fractionated by ultrafiltration. Food Bioprocess Technol, 2022, 15366982.

[79] Virgilio N, Schön C, Mödinger Y, van der Steen B, Vleminckx S, van Holthoon FL, et al. Absorption of bioactive peptides following collagen hydrolysate intake: a randomized, double-blind crossover study in healthy individuals. Front Nutr, 2024, 11: 1416643.

[80] Herregods G, Van Camp J, Morel N, Ghesquière B, Gevaert K, Vercruysse L, et al. Angiotensin I-converting enzyme inhibitory activity of gelatin hydrolysates and identification of bioactive peptides. J Agric Food Chem, 2011, 5925528.

[81] Im ST, Lee SH. Structure characterization and antihypertensive effect of an antioxidant peptide purified from alcalase hydrolysate of velvet antler. Food Sci Anim Resour, 2023, 43118494.

Funding

Thailand Science Research and Innovation (TSRI), and the National Science, Research, and Innovation Fund (NSRF)(FF3-303-68-12-43(F))

Program Management Unit for Competitiveness (PMU-C) (C02F670298)

Full-time Doctoral Researcher(FtR.69/9/2569)

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