IngredientsSerratiopeptidase is a metalloprotease enzyme with a molecular weight of 45–60 kDa. The enzyme contains zinc at the active site, and belongs to the group serralysin with an EC number of 3.4.24.40. It is a single-chain metalloprotease enzyme belonging to the serralysin family that cleaves peptide bonds in extracellular proteins and requires Zn²⁺ for catalytic activity. Alternative names include serrapeptase, serratiopeptidase, serratia protease, and serralysin.
Chemically, serratiopeptidase (SRP) is an extracellular metalloprotease derived from the non-pathogenic enterobacteria Serratia E15. It consists of a polypeptide chain of 470 residues and a catalytic zinc ion per molecule, with a molecular weight of 45–60 kDa.
The catalytic domain comprises Zn coordinated with three histidine residues (His192, His196, His202), along with glutamate (Glu193) and tyrosine (Tyr232) residues, which confirmed that the purified protein is identical to serralysin. The enzyme also contains calcium ions within its binding sites, which it uses alongside the zinc atom as integral components of its structural stability. Domain-wise, it has two domains: an N-terminal Catalytic Domain (Ncat) and a C-terminal Repeat-In-Toxin Domain (Crtx).
The enzyme has a molecular size of approximately 52 kDa and has the ability to bind with alpha-2-macroglobulin in blood at a ratio of 1:1.
Serratiopeptidase was first isolated from Enterobacterium Serratia E-15, an isolate from the gut of Bombyx mori (Miyata et al. 1970). It is reportedly produced from S. marcescens, a Gram-negative small rod belonging to the family Enterobacteriaceae.
This microorganism was originally isolated in the late 1960s from the silkworm Bombyx mori L. Serratiopeptidase is present in the silkworm intestine and allows the emerging moth to dissolve its cocoon. It is produced by purification mainly from fermentation of Serratia marcescens or Serratia sp.
Serratiopeptidase is reportedly produced from S. marcescens, a Gram-negative small rod belonging to the family Enterobacteriaceae. Although S. marcescens is one of the most common serratiopeptidase producers (Romero et al. 2001; Nam et al. 2013; Ethiraj and Gopinath 2017), other bacteria have also been reported for serratiopeptidase production.
Because serratiopeptidase is produced naturally by a bacterium (Serratia marcescens) that is pathogenic and able to spread in most environments, E. coli is used as a means of recombinant expression to produce serratiopeptidase in order to acquire higher yields of the enzyme than from its native source. These strains of E. coli are engineered to produce high yields of recombined gene expression, and are also a way to sidestep the risks of using a pathogenic bacterium in mass-scale production.
Formulations of serratiopeptidase are available mainly in the form of enteric-coated tablets (notably Danzen, produced by Takeda Japan). These tablets are conventionally dry-coated with an enteric polymer. Serratiopeptidase is reported to undergo acid hydrolysis at gastric pH, thereby decreasing its stability in the gastrointestinal tract.
The most common problem associated with oral delivery of serratiopeptidase is high risk of enzymatic degradation in the gastrointestinal tract due to its proteinaceous nature. In addition, the hydrophilic nature of serratiopeptidase leads to low intestinal membrane permeability, so a very high dosage must be orally administered to elicit significant anti-inflammatory responses.
In order to increase the stability of serratiopeptidase (via reduced acid hydrolysis) and improve oral bioavailability simultaneously, several techniques have been explored, including delivery in Eudragit S100 microspheres, liposomal formulations, alginate gel encapsulation, chitosan-coated ceramic nanocores, in situ cubic phase transforming systems of glyceryl monooleate, tetracycline-serratiopeptidase-containing periodontal gel, and polar lipid-based lipospheres.
Enzyme activity is commonly expressed in units. Serratiopeptidase 10 mg is equal to 20,000 units of enzyme activity. Serrapeptase is a commonly used drug in Japan and Europe. In the United States, serrapeptase is classified as a dietary supplement.
The initial purification and characterization of this protease were detailed in a seminal 1970 study by Miyata, Tomoda, and Maejima, who named it "Serratia protease" due to its origin from the Serratia bacterium. Subsequent research confirmed its proteolytic activity and specificity, leading to its common designation as serratiopeptidase, reflecting the bacterial genus Serratia and its peptidase function.
Japanese researchers were the first to report and introduce the anti-inflammatory drug serratiopeptidase to the world. Enzyme formulations were created and widely used as medicines. After 1970, these enzyme formulations were eventually successfully marketed worldwide.
First approved for therapeutic use in Japan in 1968, serratiopeptidase has been employed as a dietary supplement and pharmaceutical agent primarily for its anti-inflammatory, analgesic, anti-edemic, and mucolytic properties.
The use of enzymes such as trypsin, chymotrypsin, and bromelain as anti-inflammatory agents came into practice after it was observed during the 1950s in the USA that parenteral trypsin could be used to relieve post-surgical inflammation and inflammation due to traumatic injury caused by sports, as well as conditions like rheumatoid arthritis, ulcerative colitis, and atypical viral pneumonia. This observation was soon followed by the use of serratiopeptidase for its anti-inflammatory effects in Japan for the first time.
Later, during the 1960s, these parenteral enzyme formulations were replaced by enteric-coated successors for oral use. During the 1980s and 1990s it was proposed by separate research conducted in Europe and Japan that serratiopeptidase was the most effective agent in reducing inflammation among all other enzyme preparations. Serratiopeptidase has therefore been used for almost 40 years in Japan and Europe for pain and inflammation due to arthritis, trauma, surgery, sinusitis, bronchitis, carpal tunnel syndrome, and painful swelling of breasts.
Serratiopeptidase has been extensively used in Europe and Asia for more than 30 years, but is relatively new in the United States and Canada. Its anti-inflammatory property was first studied in Japan in 1967. Later, during the 1970s, these parenteral enzyme preparations were replaced by an oral enteric-coated tablet form. During the 1980s and 1990s, research conducted separately in Europe and Japan demonstrated that serratiopeptidase is the most effective agent in diminishing inflammation among all available enzyme formulations. Currently, serratiopeptidase has been broadly used in Japan and Europe as the anti-inflammatory and analgesic agent of choice.
Unlike botanical supplements containing a spectrum of phytochemicals, serratiopeptidase is itself the active entity—a single purified proteolytic enzyme. Its therapeutic properties stem entirely from this enzyme's biochemical activity.
Serratiopeptidase (EC No 3.4.24.40) has a long history in medicine and is widely used to combat various kinds of inflammation and inflammatory disorders. Serratiopeptidase, or serrapeptase, is a protein (proteolytic) enzyme isolated from the non-pathogenic enterobacteria Serratia E15 found in silkworms.
The molecular mass of the metalloprotease, as determined by SDS-PAGE, is approximately 51 kDa. The purified serratiopeptidase presents optimum activity at pH 9.0 and temperature 50°C, and shows stability across a wide pH and temperature range.
Serratiopeptidase has no known botanical origin. It is not a plant-derived compound but a microbially produced enzyme, typically manufactured through controlled fermentation processes. The proteolytic enzymes in common use today are derived from bacteria (serrapeptase grown from Serratia marcescens cultures), plants (bromelain from pineapple stem and papain from papaya), and animal sources (trypsin and chymotrypsin from hogs or cattle).
Serratiopeptidase is absorbed from the intestine, distributed to the site of inflammation via blood or lymph, and has a complex effect, exerting an anti-inflammatory effect by regulating inflammatory cytokines, which are the background for the emergence and maintenance of chronic inflammation.
Serratiopeptidase reduces swelling by the process of decreasing the amount of fluid in the tissues, thinning the fluid, and by facilitating the drainage of fluid.
Serratiopeptidase has been shown to exert anti-inflammatory effects by reducing inflammatory cytokines and adhesion molecules, thus regulating inflammatory cell movement to the site of inflammation.
Research findings have demonstrated that the enzyme possesses the unique ability to dissolve the dead and damaged tissue that is a by-product of the healing response without harming living tissues. Serratiopeptidase also works by modifying cell-surface adhesion molecules. These cell surface adhesion molecules are directly and indirectly responsible for inflammation and bringing immune cells into damaged tissues.
Serratiopeptidase may help alleviate pain by inhibiting the release of pain-inducing amines like bradykinin from inflamed tissues. The enzyme reduces exudates viscosity and inhibits hydrolysis of inflammatory mediators such as histamine, bradykinin, and serotonin.
Serratiopeptidase may be beneficial in atherosclerotic disease as it acts by breaking down fibrin and other dead or damaged tissue without harming living tissue. This could enable the dissolution of blood clots and atherosclerotic plaques.
Serratiopeptidase is known to dissolve blood clots and atherosclerotic plaques by breaking down fibrin and other dead or damaged tissue. It can also remove deposits of fatty substances, cholesterol, and cellular waste inside the arteries. It must be noted, however, that the evidence supporting the anti-atherosclerotic action remains largely anecdotal (see Section 6).
The anti-biofilm ability of serratiopeptidase is attributed to its capability of modulating the expression of adhesion molecules and reducing cell surface proteins of bacteria. It prevents biofilm formation as well as helps to disperse preformed biofilm. Its anti-biofilm ability helps to enhance the penetration of antibiotics through the resistant biofilm and hence increases susceptibility of biofilms to antibiotics.
A study by a team of Italian researchers suggests that proteolytic enzymes such as serratiopeptidase could significantly enhance the effectiveness of antibiotics against biofilm and can inhibit biofilm formation.
In addition to the mucolytic property, serratiopeptidase through oral administration in allergic conditions decreases the viscosity of the nasal mucus by improving rheological properties; thus it plays a role in mucociliary clearance. Serratiopeptidase has been found bioavailable in the nasal or tracheobronchial mucus, and it exerts proteolytic action even after oral intake.
Serratiopeptidase is reported to undergo acid hydrolysis at gastric pH, thereby decreasing its stability in the gastrointestinal tract. Serratiopeptidase is normally recommended for oral administration at a dose of 5–10 mg three times a day. The enzyme is reportedly rapidly and readily absorbed through the intestine and transported directly into the blood circulation.
There is no consensus numeric systemic bioavailability (as a percentage of intact enzyme) in humans. Published reports from manufacturers and some small studies claim measurable plasma activity after oral dosing, but independent verification and standardized unit measurements are lacking.
Possible mechanisms by which absorption might occur include limited transcytosis of intact protein, uptake of active fragments, or local intestinal effects that modulate systemic inflammation; robust evidence for routine intact enzyme systemic absorption is lacking.
Serine protease possesses a higher affinity for cyclooxygenase (COX-I and COX-II), a key enzyme associated with production of different inflammatory mediators including interleukins (IL), prostaglandins (PGs) and thromboxane (TXs).
A total of 24 studies on clinical efficacy of serratiopeptidase met the inclusion criteria of a systematic review. Serratiopeptidase is being used in many clinical specialties for its anti-inflammatory, anti-edemic, and analgesic effects.
A systematic review identified 17 published clinical studies evaluating serratiopeptidase for a broad range of indications. Most of these studies had poor methodology according to grading by the Scottish Intercollegiate Guidelines Network (SIGN) checklist. Limitations included small sample size, poorly defined enrollment criteria and outcomes, unclear statistical methods, short duration, and failure of some studies to report the dose and duration of therapy.
The evidence from clinical studies has been graded according to the SIGN checklist. The grading showed that the studies supporting the anti-inflammatory and analgesic role of serratiopeptidase are generally of poor methodology.
Serratiopeptidase has been used in surgery for traumatic and postoperative inflammation, venous inflammatory disease, cystitis, and epididymitis.
A double-blind, placebo-controlled trial evaluated use of serrapeptase in 174 patients undergoing Caldwell-Luc antrostomy for chronic sinusitis. Patients were randomized to receive placebo or serrapeptase 10 mg three times daily from the day before until five days after surgery. Swelling was evaluated by measuring the distance from ear to nose and from eye to mouth. Serrapeptase significantly reduced buccal swelling compared with placebo, as measured by the distance from ear to nose (P<0.05). Maximal swelling measured from ear to nose, which occurred 24 hours after surgery, was approximately 2 mm less with serrapeptase than placebo (P<0.01).
Two randomized controlled trials reported no reduction in swelling caused by sprained ankles, and results of studies evaluating use for pain and swelling after dental surgery are conflicting.
The challenge in analyzing current evidence stems from several factors, including the variety of dosing employed and combinations with other drugs, which together create many combinations of factors that can result in differing clinical outcomes for patients; future clinical studies that will provide unequivocal answers to the role of serratiopeptidase after dental surgeries are warranted.
Evidence strength: Weak to moderate for specific surgical contexts (e.g., sinus surgery); negative or mixed results for orthopedic injury and dental surgery.
Five studies in different otorhinolaryngology pathologies have tried to explore the mucolytic properties of serratiopeptidase. Two were placebo-controlled trials, among which one study showed serratiopeptidase reduced the symptoms of severity of pain, amount and purulence of secretions, but in the second study outcomes were unclear. Another prospective, open-label study showed serratiopeptidase reduced the viscosity but not the elasticity of secretions in patients with chronic sinusitis. Similarly, one study in chronic airway disease patients compared serratiopeptidase with a non-treatment group and concluded it reduced sputum viscosity, elasticity, and neutrophil count.
A study by Mazzone et al. (1990, n=193) found serratiopeptidase significantly improved nasal obstruction, rhinorrhea, and facial pain in chronic sinusitis patients.
An open-label study in 29 patients with chronic bronchitis and bronchiectasis reported that four weeks of treatment with serrapeptase reduced sputum volume, percent solid component, elasticity, viscosity, and neutrophil concentration.
Evidence strength: Preliminary and limited. Open-label and small trials show mucolytic benefit, but controlled evidence is sparse and methodologically weak.
A prospective trial to explore the application of serratiopeptidase in the treatment of carpal tunnel syndrome showed clinical improvement in 65% of the patients.
Other conditions evaluated in low-quality studies included postoperative or traumatic swelling, carpal tunnel syndrome, secretory otitis media, and chronic airway disease, but the resulting evidence was insufficient to evaluate the efficacy of serrapeptase for these indications.
Evidence strength: Very preliminary. A single small open-label trial with no confirmed follow-up from higher-quality studies.
A study on 70 patients with breast engorgement demonstrated that serratiopeptidase treatment resulted in moderate to marked improvement in breast pain, swelling, and induration with no adverse events reported.
Evidence strength: Low. Single clinical study, limited by small size and methodological concerns.
Serratiopeptidase has been used in dentistry as an anti-inflammatory agent and to increase antibiotic concentration at the site of infection in periodontitis and pericoronitis of wisdom teeth.
Peri-implantitis is inflammation of the soft and hard tissue of dental implants. Patients that received serrapeptase healed faster and had lower implant failure rates than patients receiving placebo or NSAIDs. Further trials need to determine the effectiveness of serrapeptase for dental implant inflammation.
Evidence strength: Preliminary and adjunctive. Positive signals in dental contexts exist but require confirmation from larger, high-quality RCTs.
Two low-quality studies evaluated serrapeptase as an adjunct to increase the penetration of antimicrobial drugs into sites of infection.
Serratiopeptidase has been shown to enhance the absorption of antibiotics and prevent biofilm formation in pulmonary tissues in patients undergoing thoracotomy. The pulmonary delivery of serratiopeptidase with levofloxacin in liposomes exerts potent antimicrobial activity against Staphylococcus aureus infections in rats and reduces bacterial resistance by inhibiting biofilm formation. This combination was found bioavailable and synergistically effective in respiratory infections and further reduced the doses of levofloxacin required for bacterial infections.
Serratiopeptidase in preclinical studies was shown to increase the levels of cefotiam in plasma and lungs in pleuritis and only in lungs in pneumonitis, and in subacute bronchitis, and to synergize the efficacy of ciclacillin, ampicillin, cephalexin, and minocycline in gingival infections caused by staphylococci.
Evidence strength: In vitro and animal models are encouraging; clinical evidence is limited to low-quality or preliminary human studies.
Serratiopeptidase is even being promoted as a health supplement to prevent cardiovascular morbidity. However, the existing scientific evidence for serratiopeptidase is insufficient to support its use as a health supplement in this role.
The evidence showing its anti-atherosclerotic effects is only anecdotal. Thus, further extensive clinical studies are needed to prove its worth as a health supplement in this area.
Evidence strength: Anecdotal only. No controlled clinical trials support anti-atherosclerotic use in humans.
Serratiopeptidase has been widely used for its anti-inflammatory effects. Research has attempted to establish a potential drug candidate for vascular inflammation in cardiovascular disorder conditions, using BALB/c mice as the most successful validated model of vascular inflammation. These findings remain preclinical and cannot be directly extrapolated to clinical recommendations.
Serratiopeptidase has been used across multiple clinical specialties:
Serratiopeptidase is a proteolytic enzyme having immense applications in therapeutic areas, validated by several in vitro, in vivo, and clinical studies as well as through anecdotal evidence. These applications are attributable to its versatile properties including anti-inflammatory, anti-biofilm, analgesic, anti-edemic, and fibrinolytic effects.
The multifaceted properties of serratiopeptidase may lead towards arthritis, diabetes, cancer and thrombolytic treatments, though most of these potential applications remain speculative or confined to early-stage research.
Serratiopeptidase is normally recommended for oral administration at a dose of 5–10 mg three times a day. Serratiopeptidase 10 mg is equal to 20,000 units of enzyme activity.
The typical dosage in trials was 30 mg/day, ranging from 10–60 mg/day. The conventional supplement range is 10–60 mg per day (commonly 10 mg to 40 mg in once or divided doses); alternatively labeled by activity units (e.g., 20,000–120,000 SPU per day depending on manufacturer).
There is no FDA-recognized RDI/DRI for serratiopeptidase. Commercial dosing is empirical and varies by product.
Between meals (on an empty stomach) is commonly recommended for systemic effects — typically 30–60 minutes before meals or two hours after meals — to minimize competition with dietary proteins.
Serrapeptase was well tolerated in short-term clinical trials enrolling more than 1,400 patients, with an incidence of adverse effects similar to that seen with placebo. However, studies lasting only one to two weeks do not provide long-term safety data.
The existing scientific evidence for serratiopeptidase is insufficient to support its use as an analgesic and health supplement. The data on long-term safety of this enzyme is lacking.
The most frequently reported adverse effects of serratiopeptidase involve the gastrointestinal (GI) tract. These effects are common to many oral medications and are generally manageable. Nausea and vomiting can occur. Diarrhea is a common complaint. Some individuals experience abdominal cramps, bloating, or general discomfort. Reduced desire to eat has been reported in some patients. These GI side effects are typically mild and often resolve on their own.
Rare, serious adverse effects reported with serrapeptase include eosinophilic pneumonitis, bullous pemphigoid, hemorrhage in a patient with Behçet disease, and possibly Stevens-Johnson syndrome.
Eosinophilic pneumonitis is a rare but serious adverse effect that has been documented in a number of case reports, primarily in Japan. It is a type of allergic or hypersensitivity reaction in the lungs, where a specific type of white blood cell (eosinophil) accumulates in the lung tissue. In Japan, at least four cases of eosinophilic pneumonia have been reported with serrapeptase.
Drug-induced pneumonitis or acute eosinophilic pneumonia, presenting with fever, cough, and breathlessness, sometimes requires hospitalization and steroid treatment. Severe skin reactions such as bullous pemphigoid or Stevens-Johnson syndrome, characterized by blistering, peeling skin, and mucosal involvement, have been reported.
Due to its fibrinolytic properties (ability to break down fibrin), serratiopeptidase can interfere with blood clotting. This can increase the risk of bleeding.
Serrapeptase may increase the risk of bleeding if coadministered with anticoagulants or antiplatelet drugs. Because serratiopeptidase has fibrinolytic and possible antiplatelet effects, it may increase bleeding risk when combined with prescription anticoagulants (such as warfarin, apixaban, rivaroxaban, dabigatran), antiplatelet drugs (such as aspirin, clopidogrel), and other supplements with bleeding risk (such as high-dose fish oil, garlic, ginkgo, or turmeric).
There are no published clinical studies formally reporting drug interactions. The risk of interaction with anticoagulants is currently extrapolated from the enzyme's mechanism of action rather than from observed pharmacokinetic studies.
Individuals who are pregnant, breastfeeding, children, and those with bleeding disorders, severe lung disease, or known enzyme allergies should generally avoid serratiopeptidase unless a specialist advises otherwise.
In the U.S., serrapeptase is classified as a dietary supplement. The FDA has not approved serrapeptase for the treatment of any disease. As with other supplements, manufacturers must ensure product safety and truthful labeling; disease claims would render the product a drug and subject it to different regulatory requirements.
No NIH/NCCIH monograph endorses serrapeptase as an evidence-based treatment for specific conditions. The Office of Dietary Supplements (ODS) does not maintain a specific recommended intake for serrapeptase.
Serrapeptase is a commonly used drug (Takeda Chemical Industries) in Japan and Europe. Formulations of serratiopeptidase are available mainly in the form of enteric-coated tablets (Danzen, Takeda Japan). In Japan, it has been approved as a pharmaceutical drug and prescribed across multiple medical specialties.
Serrapeptase is no longer legally available for sale as a food supplement in the UK and EU. It was banned in 2022 after being classified as an unauthorised "novel food," which requires specific safety assessments that have not been met.
The Food Standards Agency made local authorities aware that food supplements containing serratiopeptidase (serrapeptase) constitute an unauthorised novel food. The FSA is not aware of a significant history of consumption of serratiopeptidase in the UK and EU prior to 15 May 1997.
To be legally marketed, all novel foods must undergo a rigorous pre-market safety assessment and receive authorization from the European Commission, a process now managed by the European Food Safety Authority (EFSA). As serrapeptase has not received this authorization, placing it on the market as a food or dietary supplement is illegal under EU and UK regulations. This has led to withdrawal notices and enforcement actions, effectively removing it from the legitimate supplement market for humans.
Efforts toward global regulatory harmonization are hindered by challenges in standardizing serratiopeptidase's enzyme activity, as variations in measurement units (e.g., proteolytic units per milligram) and formulation stability across production methods complicate consistent quality assurance and international pharmacopeial alignment. This lack of uniformity contributes to divergent approval processes and trade barriers between regions.
Serratiopeptidase is a proteolytic enzyme having significant applications in therapeutic areas, validated by several in vitro, in vivo, and clinical studies as well as through anecdotal evidence. These applications are attributable to its versatile properties including anti-inflammatory, anti-biofilm, analgesic, anti-edemic, and fibrinolytic effects. The significant impact reported needs to be backed by more scientific data.
Serrapeptase is used in many clinical studies against various diseases for its anti-inflammatory, fibrinolytic, and analgesic effects. There is insufficient data regarding the safety of the enzyme as a health supplement. Data about the anti-atherosclerotic activity, safety, tolerability, efficacy, and mechanism of action of serrapeptase are still required.
Among the 17 clinical studies identified by one systematic review, only five were randomized controlled trials published in English with a low risk of bias. The overall body of clinical evidence for serratiopeptidase is therefore characterized by small sample sizes, methodological limitations, short study durations, and inconsistent outcomes across specialties. Larger, well-designed, adequately powered, and independently replicated RCTs are needed to establish definitive efficacy and safety across its proposed indications.
Health conditions that Serratia may help support.
Body systems that Serratia may help support.
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