LL-37
Cathelicidin Antimicrobial Peptide LL-37 (hCAP18/LL-37)
The only human cathelicidin antimicrobial peptide, a 37-residue cationic alpha-helical peptide cleaved from hCAP18 with broad-spectrum antimicrobial, immunomodulatory, and wound healing activity. Limited but real human interventional evidence includes a positive diabetic-foot-ulcer RCT, a completed Phase 1/2 intratumoral melanoma trial, and an exploratory oral COVID-19 preprint (DOI 10.1007/s00011-025-02005-8; PMID 37480520; NCT02225366; DOI 10.1101/2020.05.11.20064584).
Last updated: 2026-03-10
Safety Summary
Human adverse-event data are sparse. In the DFU RCT, no safety concerns were noted over 4 weeks of topical use (PMID 37480520). In the melanoma trial, no serious adverse events occurred in 3 patients over up to 8 weeks of intratumoral injection (NCT02225366). In the oral cas001 pilot, no adverse reactions were reported in 11 patients over 3 weeks (DOI 10.1101/2020.05.11.20064584). In preclinical rat toxicity testing at 100x clinical dose, no adverse effects on body weight, food intake, or blood parameters were observed (DOI 10.1101/2020.05.11.20064584). However, source reviews describe LL-37 as cytotoxic to multiple human cell types at 1-10 microM via caspase-independent AIF-mediated apoptosis, preferentially targeting infected/weakened cells (DOI 10.1007/s00011-025-02005-8). At very high concentrations (as in psoriatic lesions, up to 300 microM), LL-37 drives rosacea-like skin inflammation via NLRP3 activation (DOI 10.1007/s00011-025-02005-8). LL-37 triggers mast cell degranulation via MrgX2 receptors (DOI 10.1007/s00011-025-02005-8). FDA flags immunogenicity, peptide-related impurity concerns, limited safety information, possible detrimental male-reproductive effects, and protumorigenic findings in some tissues. LL-37 from macrophages promotes colorectal cancer cell proliferation via Wnt/beta-catenin pathway activation in vitro (PMID 29936765).
Known Side Effects
common
Not established in available literature
common
uncommon
uncommon
Who Should NOT Use This
FDA states that nonclinical findings suggest Cathelicidin LL-37 can be protumorigenic in some tissues. LL-37 from macrophages promoted colorectal cancer cell proliferation via Wnt/beta-catenin signaling in vitro (PMID 29936765). LL-37 has context-dependent pro- and anti-tumorigenic effects depending on cancer type (DOI 10.1155/2020/8349712).
LL-37 drives rosacea-like skin inflammation via NLRP3 inflammasome activation. Very high concentrations of LL-37 are found in rosacea lesions (DOI 10.1007/s00011-025-02005-8).
Psoriatic lesions contain extremely high LL-37 concentrations (up to 300 microM). LL-37 triggers inflammasome activation in keratinocytes in psoriatic lesions (DOI 10.1007/s00011-025-02005-8).
LL-37 activates the NLRP3 inflammasome, and NET-associated LL-37 enhances inflammasome activation in lupus macrophages (DOI 10.1007/s00011-025-02005-8). May exacerbate autoimmune inflammation.
FDA notes nonclinical research findings suggest detrimental effects on male reproduction. No human data available to assess this risk.
Talk to Your Doctor
Before considering LL-37, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-15]
Evidence Assessment
Tier 3: The source corpus contains one published randomized, double-blind, controlled human trial showing positive wound-healing signal in diabetic foot ulcers (PMID 37480520; NCT04098562), one completed Phase 1/2 melanoma trial with posted results in 3 patients (NCT02225366), one small uncontrolled oral preprint in COVID-19 (DOI 10.1101/2020.05.11.20064584), and one Phase 2 RCT (N=390) using vitamin D plus phenylbutyrate to boost endogenous LL-37 in TB patients with positive clinical results (NCT01698476, PMID 29696707). Multiple in vitro and animal studies support the mechanisms. No Phase 3 program or approval-level evidence exists.
1Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer: a randomized double-blind controlled trialNCT04098562PMID 37480520
Miranda Eliza et al. - Archives of Dermatological Research (2023) - randomized double-blind controlled trial - Registry planned N=40 (NCT04098562); exact analyzed N not stated in abstract
Topical 0.5 mg/mL LL-37 cream applied twice weekly for 4 weeks increased granulation index versus placebo at days 7, 14, 21, and 28 (p=0.031, 0.009, 0.006, 0.037). Baseline wound LL-37 levels were equally low in both groups. Did not significantly reduce IL-1alpha, TNF-alpha, or aerobic bacterial colonization.
Limitations: Exact analyzed sample size not stated in abstract. Short 4-week follow-up. Cytokine and bacterial endpoints were not significant. Single-center (Jakarta).
2Induction of Antitumor Response in Melanoma Patients Using the Antimicrobial Peptide LL37NCT02225366
MD Anderson Cancer Center - ClinicalTrials.gov (2014) - Phase 1/2 single-group clinical trial - N=3 evaluable (2 in Cohort 1 at 250 ug/tumor, 1 in Cohort 2 at 500 ug/tumor; 4 enrolled per registry)
Weekly intratumoral LL-37 injections for up to 8 weeks in patients with cutaneous/subcutaneous melanoma. No serious adverse events. No deaths. No dose-limiting toxicity at either dose level. Primary outcome: OBD identified. Secondary outcome: antitumor immune response observed in all evaluable patients. Other AEs: 1 squamous cell carcinoma, actinic keratosis. Results posted 2021-12-09.
Limitations: Very small sample (N=3 evaluable). Single-arm dose-finding design. No efficacy conclusion possible at this sample size.
3Preliminary evaluation of the safety and efficacy of oral human antimicrobial peptide LL-37 in the treatment of patients of COVID-19, a small-scale, single-arm, exploratory safety study [PREPRINT]
Zhang H et al. - medRxiv (preprint) (2020) - single-arm pilot safety study - N=11 (5 male, 6 female; age 55+/-12)
Oral cas001 (genetically modified L. lactis producing LL-37, 1x10^9 CFU/capsule, 3 capsules 3x daily for 3 weeks) was safe and well-tolerated. No adverse reactions. Serum LL-37 peaked 2 hours after administration and returned to baseline by 6 hours. Possible improvement in GI and respiratory symptoms. Preclinical rat study at 100x clinical dose showed no adverse effects.
Limitations: Preprint, NOT peer-reviewed. Single-arm with no control group (N=11). Too small for efficacy conclusions.
4Daily adjunctive therapy with vitamin D3 and phenylbutyrate supports clinical recovery from pulmonary tuberculosis: a randomized controlled trial in EthiopiaNCT01698476PMID 29696707
Bekele A et al. - Journal of Internal Medicine (2018) - Phase 2 RCT - N=390 (randomized, double-blind, placebo-controlled)
Vitamin D 5000 IU daily + sodium phenylbutyrate 500 mg twice daily for 16 weeks as adjunctive therapy to standard anti-TB treatment improved clinical composite TB score at 8 weeks vs placebo. LL-37 levels measured as secondary endpoint.
Limitations: Indirect evidence for exogenous LL-37 -- this trial boosted endogenous production via vitamin D + PBA.
5Human antimicrobial/host defense peptide LL-37 may prevent the spread of a local infection through multiple mechanisms: an update
Svensson D, Nilsson BO - Inflammation Research (2025) - review - N/A (review)
Comprehensive review of LL-37 mechanisms. Covers direct membrane permeabilization, endotoxin neutralization, biofilm disruption, NET promotion, immune cell chemotaxis, receptor signaling (FPR2, P2X7, EGFR, MrgX2), NLRP3/AIM2 inflammasome effects, cytotoxicity (1-10 microM, AIF-mediated), and vitamin D regulation of LL-37 production.
Limitations: Narrative review; primarily covers in vitro data with human cells.
6LL37 promotes angiogenesis: a potential therapeutic strategy for lower limb ischemic diseases
Yang Y et al. - Frontiers in Pharmacology (2025) - in vitro and animal study - 24 mice plus HUVEC experiments
Exogenous LL-37 increased HUVEC proliferation, migration, and angiogenesis, improved blood-flow recovery in ischemic mouse limbs, raised CD31 and CD34 expression, and increased VEGFA plus PI3K/AKT/mTOR signaling.
Limitations: Preclinical only. Not a human wound or infection trial.
7Evaluation value of human antibacterial peptide LL-37 on the prognosis of elderly patients with sepsisPMID 30541637
Chinese authors (published in Chinese) - Chinese Critical Care Medicine (2018) - prospective observational cohort - N=113 elderly sepsis patients + 32 healthy controls + 31 pneumonia controls
LL-37 negatively correlated with APACHE II (r=-0.329, P=0.007) and SOFA (r=-0.344, P=0.005). Day-7 declining LL-37 predicted 28-day mortality: AUC=0.670 at cutoff 1283.0 microg/L. 52.2% (59/113) 28-day mortality.
Limitations: Published in Chinese. Single-center. Observational biomarker study, not therapeutic.
8Clinical significance of antibacterial peptide LL-37 in early diagnosis of patients with sepsis in emergency departmentPMID 31657329
Chinese authors (published in Chinese) - Chinese Critical Care Medicine (2019) - prospective observational study - N=40 sepsis patients + 20 healthy volunteers
LL-37 significantly elevated in sepsis vs controls. Combined LL-37+PCT+CRP achieved AUC=0.994 with 97.5% sensitivity and 95.0% specificity for sepsis diagnosis.
Limitations: Published in Chinese. Small sample. Observational/diagnostic, not therapeutic.
9Antimicrobial peptide LL-37 in macrophages promotes colorectal cancer growthPMID 29936765
Chinese authors (published in Chinese) - Chinese Journal of Oncology (2018) - in vitro - N/A (SW480, HCT116 colorectal cancer cells co-cultured with macrophages)
Macrophage-derived LL-37 increased SW480 proliferation via Wnt/beta-catenin pathway activation. Anti-LL-37 antibodies reversed the effect.
Limitations: Published in Chinese. In vitro only.
10Regulation of virulence factors of Pseudomonas aeruginosa by Scutellaria baicalensis, Prunella vulgaris and antimicrobial peptide LL-37PMID 41637127
Xiao Q et al. - Journal of Medical Microbiology (2026) - in vitro - N/A (PAO1 and PA-deltaLasI/rhlI strains)
LL-37 significantly reduced P. aeruginosa elastase secretion and downregulated quorum sensing genes lasI and rhlR without affecting bacterial proliferation.
Limitations: In vitro. Laboratory strains only.
11LL-37 in periodontal health and disease and its susceptibility to degradation by proteinases present in gingival crevicular fluidPMID 23952216
McCrudden MTC et al. - Journal of Clinical Periodontology (2013) - ex vivo / clinical - Periodontitis patients and healthy subjects (exact N not specified in abstract)
LL-37 detectable in GCF. Concentration higher in periodontitis. GCF from P. gingivalis positive sites rapidly degraded synthetic LL-37 via gingipain activity.
Limitations: Small study. Exact sample size not stated.
12Gingival crevicular fluid levels of cathelicidin LL-37 and interleukin-18 in patients with chronic periodontitisPMID 19485828
Turkoglu O et al. - Journal of Periodontology (2009) - clinical observational - N=59 subjects (chronic periodontitis, gingivitis, healthy controls)
GCF LL-37 significantly elevated in chronic periodontitis vs gingivitis and healthy controls. Positive correlation with probing depth, clinical attachment level, plaque index, and bleeding index.
Limitations: Cross-sectional. Small sample. Cannot determine causality.
13Effects of antimicrobial peptide LL-37 expressed and purified from prokaryotes in the murine model of vaginal candidiasisPMID 27465873
Chinese authors (published in Chinese) - Chinese journal (2016) - animal study (murine) - N=30 female Kunming mice (15 per group)
Intravaginal recombinant LL-37 significantly reduced C. albicans CFU (P=0.017). Increased IFN-gamma, decreased IL-10, improving IFN-gamma/IL-10 ratio.
Limitations: Published in Chinese. Animal study only. Small sample.
14Influence of antimicrobial peptide biofunctionalized TiO2 nanotubes on the biological behavior of human keratinocytes and its antibacterial effectPMID 36746450
Chinese authors (published in Chinese) - Chinese journal (2023) - in vitro - N/A (HaCaT cells, P. gingivalis)
LL-37-loaded TiO2 nanotubes enhanced HaCaT cell migration to 96.4+/-4.9% wound closure at 24h with potent antibacterial activity against P. gingivalis.
Limitations: Published in Chinese. In vitro. Specific to dental implant application.
15Injectable self-healing hydrogel loaded with a self-assembling LL-37 derivative for treating infected skin woundsPMID 41653943
Ba Q et al. - International Journal of Pharmaceutics (2026) - preclinical (in vitro + animal) - N/A (murine full-thickness wound model)
LL-37 derivative FR-20 in chitosan hydrogel showed potent bactericidal activity against E. coli and MRSA with accelerated wound healing in mouse model.
Limitations: Uses LL-37 derivative (FR-20), not native LL-37. Animal model only.