LL-37

LL-37 is the only cathelicidin antimicrobial peptide produced in humans ¹. It begins as an inactive precursor called hCAP-18 stored in neutrophils and epithelial cells. When those cells release the precursor, an enzyme called proteinase 3 clips the C-terminal end into the active 37-amino-acid peptide ⁶. Expression appears in airway, skin, gut, and genitourinary lining as well as immune cells ².

In laboratory research, LL-37 acts as a broad-spectrum membrane-active antimicrobial and as an immune signal. It is disordered in water and folds into a helix when it contacts membranes, which lets it assemble into pore-forming structures on microbial surfaces ². The same molecule also recruits immune cells and modulates tissue repair through the FPRL1/FPR2 and P2X7 receptors ⁸.

The strongest efficacy evidence is preclinical. Recombinant LL-37 was active against all 43 clinical bacterial isolates in one testing panel ⁴, and animal models show benefits in sepsis, infected wounds, and diabetic wound repair ¹⁰. Human data are observational biomarker and expression studies; no human efficacy trial of injected LL-37 had been completed as of the available literature ⁵.

LL-37 works on two tracks. The first is direct membrane disruption. The peptide is positively charged (+6) and folds from a loose coil into an amphipathic helix at lipid membranes ⁹. It prefers negatively charged microbial surfaces rich in phosphatidylglycerol and cardiolipin, while cholesterol-rich human membranes resist it. Depending on the lipids present, it can form ion-conducting pores, peptide-lipid nanofibres, or carpet-like membrane dissolution ⁵⁶. In some pathogens, docking is specific. For Acinetobacter baumannii, binding to outer membrane protein OmpA correlates with killing and reduced adhesion ⁶⁰.

The second track is receptor signaling. LL-37 attracts neutrophils, monocytes, and T cells through the formyl peptide receptor-like 1 (FPRL1), now often called FPR2 ⁸. It also directly opens the P2X7 ion channel on immune and barrier cells ⁶². In neutrophils, combined FPRL1/P2X7 activation delays apoptotic cell death at low concentrations by increasing Bcl-xL and limiting caspase-3 activity ¹⁹. In keratinocytes, P2X7 signaling amplifies chemokine responses to microbial signals ⁶³. These receptor actions explain why effects are context-dependent: pro-inflammatory in rosacea and psoriasis, barrier-protective in the gut and airway, pro-angiogenic in wounds, and mixed in cancer ²⁷.

Secondary research findings include:

• Endotoxin neutralization and sepsis survival in mouse models via LPS binding, reduced macrophage pyroptosis, and release of antimicrobial NETs and ectosomes ²⁰.
• Nucleic acid complexation in psoriasis and SLE where LL-37 delivers self-RNA or DNA to immune sensors and drives type I interferon ²³.
• Autophagy induction required for wound repair in macrophages and keratinocytes via P2X7/AMPK/ULK1 and TFEB pathways ²¹.
• Angiogenesis in wound tissue ⁶⁶, with anti-angiogenic action in gastric cancer via NF-kB/IL-6 ²⁹.
• Endogenous induction by vitamin D3 and butyrate ⁴⁰.

Antimicrobial activity

Recombinant LL-37 was active against all 43 clinical bacterial isolates in a standard in vitro panel ⁴. In a mouse systemic Acinetobacter baumannii infection model, LL-37-treated mice survived and cleared bacteremia ¹⁰. In MRSA-infected surgical wounds, topical plus intraperitoneal LL-37 improved re-epithelialization, granulation, collagen organization, and new vessel formation ¹¹. Against carbapenem-resistant Pseudomonas aeruginosa, LL-37 alone has a high MIC of 256 µg/mL, but low doses potentiate carbapenems 4-16× ⁶⁸.

Antifungal and antiviral research shows activity against multidrug-resistant Candida auris with MICs of 25-100 µg/mL and 100% synergy with amphotericin B and caspofungin ¹⁶. A notable exception is Aspergillus fumigatus, where LL-37 and related fragments can stimulate fungal growth and toxin production ¹⁸. Against viruses, LL-37 inactivated Rift Valley fever virus and reduced infection in vitro ¹³, and analogs blocked enterovirus EV71 entry and uncoating ¹⁴.

Wound and tissue repair

LL-37 plus adipose-derived stem cells accelerated diabetic wound closure beyond either alone, and diabetic human wounds show deficiency of the LL-37 precursor CAMP ²⁴. TFEB-dependent autophagy in keratinocytes is one mechanism ²⁵. A 20 µg dose delivered in chitosan hydrogel improved pressure-ulcer closure and increased HIF-1α/VEGF-A in a mouse model ²⁶.

Immune and biomarker signals

LL-37 recruits immune cells ⁸ and extends neutrophil lifespan at low concentrations ¹⁹. In a mouse sepsis model, it suppressed macrophage pyroptosis and improved survival ²⁰. Human observational data show gingival crevicular fluid LL-37 rises with periodontitis severity ³⁷, and salivary LL-37 differentiates oral cancer with 100% sensitivity and 90% specificity ³⁹. Elevated serum LL-37 tracks inflammatory disease states such as psoriasis, tuberculosis, and pulmonary infections rather than indicating benefit ⁴¹.

Other effects

In an ovariectomized rat model, systemic LL-37 restored bone metabolic balance through Wnt/β-catenin ⁴⁸. It also binds islet amyloid polypeptide with nanomolar affinity and suppresses amyloid assembly in vitro ⁴⁹.

No human randomized efficacy trial of exogenous LL-37 exists. Human dosing patterns described in the documents are community protocols; animal studies provide the efficacy anchors. The timeline accompanying this page reflects one common community systemic protocol.

Key protocol patterns from the research:

• Systemic immune and tissue repair: community protocols commonly use 250-500 mcg subcutaneously once daily for 4-8 weeks, starting at 250 mcg and titrating to 500 mcg only if tolerated, followed by 2-4 weeks off. These figures are practitioner consensus, not regulatory labeling.
• Mouse systemic infection models: published work with Acinetobacter baumannii used parenteral LL-37 and showed survival with bacterial clearance ¹⁰. Sepsis models used single or short courses ²⁰.
• Wound models: a 20 µg dose in 2.5% chitosan hydrogel per ulcer bed improved pressure-ulcer closure in mice ²⁶. MRSA wound models combined topical and intraperitoneal administration ¹¹. Diabetic wound models showed benefit from LL-37 plus stem cells ²⁴.
• Community weight-stratified range: 150-250 mcg daily for 50-64 kg, 250-400 mcg daily for 68-82 kg, and 350-500 mcg daily for 84-100 kg. No weight-based pharmacokinetic validation exists for these figures.

Route comparisons from the documents: subcutaneous is the most supported parenteral route because biodistribution studies show two-phase absorption and uptake into lymph nodes and spleen ⁵². Topical or hydrogel delivery has the strongest wound-efficacy evidence ¹¹. Oral delivery is not viable without engineered carriers due to gut proteolysis and mucosal clearance ⁵. There are no human chronobiology data; schedule consistency matters more than clock time.

LL-37 is supplied as a lyophilized powder. In research settings, reconstitution uses bacteriostatic water or sterile water. Water-based diluents are preferred over saline or PBS because salt promotes peptide self-association, which changes activity and handling ⁵⁵. Allow the vial to reach room temperature, add diluent slowly down the vial wall, and swirl gently rather than vortexing. This limits foaming of the amphipathic peptide and reduces aggregation.

Store unreconstituted peptide frozen and protected from light for long-term holding. After reconstitution, refrigerate and use within 7-14 days in community practice. Avoid repeated freeze-thaw cycles because LL-37 has low proteolytic stability and tends to self-associate with salt or temperature stress ⁵⁵. Do not pre-dilute into serum, plasma, saliva, or other biological matrices for storage; these matrices inactivate the peptide ⁸⁷.

The interactive calculator in this section handles the dilution math for a selected vial size, diluent volume, and target dose.

Most interaction evidence is in vitro or animal-level; no human interaction studies were available ⁵.

Antimicrobial combinations

• Beta-lactam sensitization: sub-inhibitory nafcillin enhances LL-37 killing of MSSA, while vancomycin lacks the effect ¹². Similar sensitization applies to methicillin-resistant S. epidermidis with nafcillin plus daptomycin ⁸⁰.
• Carbapenems: LL-37 or its derivative RP557 at one-quarter MIC increased susceptibility of carbapenem-resistant P. aeruginosa 4-16× ⁶⁸.
• Phage endolysin Ply2660 shows synergy against vancomycin-resistant E. faecalis biofilms and improved outcomes in a mouse septicemia model ⁷⁹.
• Antifungals: 100% synergy with amphotericin B and caspofungin against C. auris, and 70% with fluconazole ¹⁶.
• Cancer drugs: LL-37 synergized with etoposide against glioma cells and shared temozolomide-like mitochondrial suppression in glioma cells ³².

Host and supplement interactions

• Vitamin D3 and butyrate are the main endogenous inducers of LL-37, and low vitamin D tracks with low LL-37 in active tuberculosis ⁴⁰.
• Statins may raise epithelial LL-37/hCAP-18 ⁸⁴.
• Smoking lowers gingival crevicular fluid LL-37 in periodontitis ⁸⁶.
• Corticosteroid interaction: LL-37 restored budesonide responsiveness in a smoking plus LPS airway inflammation model ⁸².
• mTOR inhibitors: rapamycin abolished LL-37 growth inhibition in pancreatic cancer models, since the effect depends on mTOR-mediated autophagy suppression ³¹.
• Interferon-based immunotherapy: LL-37 suppresses IFN-gamma responses in antigen-presenting cells, so the combination direction is theoretically antagonistic ⁹¹.

Peptide combinations

• HNP-1 and LL-37 heteroaggregate, which modulates both activities and neutralizes cytotoxicity, making same-vial mixing unpredictable ⁹⁰.
• Community stacks with BPC-157 or TB-500 for wound healing are reported, with no formal interaction data. Avoid co-injecting multiple cationic membrane-active peptides at cytotoxic concentrations.

LL-37 is not a hormonal anabolic; no randomized trial defines a cycle. Community protocols commonly follow a standard pattern: start at 250 mcg subcutaneously once daily, titrate to 500 mcg after the first week if tolerated, continue for 4-6 weeks, then take 2-4 weeks off. Shorter gut-barrier pulses use 250 mcg daily for 2-3 weeks with 1-2 weeks off. These are practitioner and community data, not regulatory guidance.

Why cycles exist

The rationale is concentration-dependent cytotoxicity rather than receptor tolerance. LL-37 is cytotoxic to many human cell types at 1-10 µM, while inflamed tissue can reach about 1 µM in gingival crevicular fluid and around 300 µM in psoriatic lesions ¹. Other documented cycle drivers include:

• Autoimmune complex risk: LL-37 bound to self-DNA or self-RNA drives type I interferon in psoriasis and SLE ²³.
• Cancer duality: suppressive in some cancer models, pro-metastatic in hepatocellular carcinoma models ²⁹.
• Vascular effects: LL-37 induces endothelial-to-mesenchymal transition in vitro ⁶⁷.
• Microbial adaptation and aggregation concerns, which favor intermittent exposure over continuous pressure.

Signals to reassess

Injection-site erythema, flushing, or rosacea-like flares ⁴⁵; paradoxical symptom worsening; new joint aches, rash, or fatigue; plateaued wound or gut improvements after weeks 4-6; any new suspicious skin lesion or cancer diagnosis.

Community stacks most often pair LL-37 with BPC-157 or TB-500 for wound healing and blood vessel support, although no controlled interaction data exist for these combinations. Mechanistically, LL-37 is pro-angiogenic in wound tissue ⁶⁶, which makes it a candidate partner for structural repair peptides when used under research protocols.

Documented combinations include:

• LL-37 plus adipose-derived stem cells accelerated diabetic wound closure beyond either alone in mouse work ²⁴.
• LL-37 plus HNP-1 heteroaggregates and neutralizes cytotoxicity, but the altered activity profile makes same-vial storage unpredictable ⁹⁰.
• Antimicrobial stacks with beta-lactams, carbapenems, antifungals, or phage endolysin are the best-characterized synergy profiles ¹².
• In oncology models, LL-37 can synergize with etoposide or share metabolic suppression with temozolomide-like effects in glioma cells ³², but cancer direction is tissue-dependent ²⁷.

Precaution from the interaction documents: multiple cationic membrane-active peptides should not be co-injected in one formulation at cytotoxic concentrations because aggregation and membrane-selectivity changes are documented ⁹⁰.

LL-37 has no FDA or EMA approval for any indication. It is not scheduled under the Controlled Substances Act in the United States, and it carries no DEA schedule designation ⁵. Supply occurs mainly as research-grade peptide or through prescription compounding, where availability has varied with tightened FDA oversight of peptide compounding. No approved product means no official labeling, standardized dose, or post-marketing surveillance ⁵.

Internationally, no centralized marketing authorization exists. In the UK LL-37 is an unlicensed medicine, and Australia treats cathelicidin peptides as prescription-only Schedule 4 substances with strict import controls. EU and Canadian status is similarly unapproved and restricted to research or clinic channels.

Anti-doping: LL-37 is not expressly named on the WADA Prohibited List, but as a non-approved substance it falls under S0 and is prohibited at all times. The earlier report of LL-37 as an insulin-like growth factor-1 receptor agonist, which would have supported S2 classification, was formally retracted ¹⁰⁰. S0 is the operative prohibition.

Common effects

The dominant documented risk is dose-dependent host-cell toxicity. LL-37 is cytotoxic to many human cell types at 1-10 µM in vitro, while physiological concentrations range from about 1 µM in gingival crevicular fluid to roughly 300 µM in psoriatic lesions ¹.

Local injection-site reactions such as transient redness, stinging, and short-lived itching are the most reported effects in community protocols. They are mechanically consistent with LL-37 mast cell chemotaxis ⁷² and COX-2-dependent neutrophil recruitment ⁷⁷.

Barrier disruption is documented: LL-37 transiently increased colonic epithelial permeability by degrading occludin and claudin-2 at sub-microbicidal concentrations ⁴⁷.

Uncommon and serious signals

• Rosacea-like flares: LL-37 activates primed NLRP3 inflammasomes and drives the rosacea phenotype in models ⁴⁵.
• Autoimmune complex pathway: LL-37 with self-DNA or self-RNA drives type I interferon in psoriasis and SLE ²³.
• Fungal stimulation: A. fumigatus growth and gliotoxin production increased in cystic fibrosis-relevant models ¹⁸.
• Cancer promotion in certain models: hepatocellular carcinoma EMT and lung metastasis ³⁰, plus growth factor activity in ovarian, lung, breast, prostate, melanoma, and pancreatic models ²⁷.
• Vascular effects: endothelial-to-mesenchymal transition via Akt/NF-kB ⁶⁷. Anti-LL-37 IgG associates with prior myocardial infarction in observational data ⁷³.

Caution populations

Relative cautions in research protocols include active SLE or severe psoriasis, rosacea-prone skin, known Aspergillus colonization or cystic fibrosis lung disease, advanced atherosclerosis, active malignancies outside those where research shows suppression, colitis, and severe renal or hepatic impairment. No pregnancy, lactation, or pediatric safety data exist.

Monitoring

Community-informed baseline testing includes CBC with differential, 25-hydroxyvitamin D, CRP, liver and renal panels, and autoantibody screening where autoimmune history exists. During injectable use, CBC and CRP at about 4-week intervals and liver/renal panels monthly are common. Topical use generally does not require bloodwork.