LL-37

I. Introduction

The Innate Immune System and Antimicrobial Peptides (AMPs)

The innate immune system constitutes the body’s first and most immediate line of defense against pathogenic microorganisms.1 This evolutionarily ancient system provides a rapid, non-specific response, relying on a repertoire of germline-encoded receptors and effector molecules to recognize and eliminate threats without prior sensitization.3 A critical component of this defense is a vast arsenal of antimicrobial peptides (AMPs), small, gene-encoded polypeptides that form a chemical shield at epithelial surfaces and within phagocytic cells.1 In mammals, these peptides are broadly categorized into two major families: the defensins and the cathelicidins, both of which are central to host defense.1

The Cathelicidin Family and the Uniqueness of LL-37

The cathelicidin family is structurally defined by a highly conserved N-terminal pro-sequence known as the “cathelin” domain and a highly variable C-terminal domain that, upon cleavage, becomes the active antimicrobial peptide.5 While many mammalian species, such as cows and pigs, express a diverse array of cathelicidins, humans are unique in possessing only a single gene for this family,

CAMP.5 This gene encodes the precursor protein hCAP18, which is processed to yield the active 37-amino-acid peptide, LL-37.4 This singularity in the human genome suggests that significant evolutionary pressure has consolidated a wide spectrum of host defense functions into this one molecule. This functional condensation is likely the fundamental reason for its pleiotropic (possessing multiple, diverse functions) nature; LL-37 is tasked with responsibilities that may be distributed across several specialized peptides in other species.

Thesis: The “Double-Edged Sword” of LL-37

The profound functional density of LL-37 positions it as a quintessential “double-edged sword” in human immunology. On one hand, it is an indispensable component of host defense, acting as an “alarmin”—a danger signal released upon tissue injury or infection that not only directly kills pathogens but also orchestrates a complex immune and regenerative response.1 On the other hand, this very potency makes it a formidable driver of pathology when its expression, processing, or localization is dysregulated. Sustained high levels or aberrant forms of the peptide can transform its protective functions into pathogenic ones, contributing to chronic inflammation, the breakdown of self-tolerance in autoimmune diseases like psoriasis and lupus, and the progression of certain cancers.2 A single stimulus, such as tissue damage, triggers a molecule that simultaneously initiates inflammation, recruits immune cells, kills microbes, and promotes tissue remodeling. In an acute, self-limiting context, this is a highly efficient system. However, in a chronic setting, the same molecule can inadvertently perpetuate inflammation and promote aberrant cell growth, explaining its contradictory roles. This report will systematically deconstruct the dichotomous nature of LL-37, from its molecular biology to its complex roles in health and disease, and evaluate its standing as a promising but challenging therapeutic candidate.

II. Molecular Profile and Biogenesis of LL-37

The CAMP Gene and hCAP18 Precursor Protein

The biological journey of LL-37 begins with the CAMP (Cathelicidin Antimicrobial Peptide) gene, located on human chromosome 3p21.6 Transcription and translation of this gene yield an 18 kDa pre-pro-protein known as hCAP18 (human Cationic Antimicrobial Protein of 18 kDa).6 This inactive precursor is structurally organized into three distinct domains:

An N-terminal signal peptide (30 amino acids) that directs the protein for secretion and processing.
A highly conserved, 103-amino-acid pro-sequence known as the cathelin-like domain.
A C-terminal, 37-amino-acid domain which, upon cleavage, becomes the biologically active LL-37 peptide.6

hCAP18 is synthesized and stored as an inert reservoir in specific cellular compartments, primarily within the secondary granules of neutrophils and the lamellar bodies of keratinocytes (the primary cells of the skin’s outer layer), poised for rapid release and activation in response to inflammatory or infectious stimuli.2

Proteolytic Activation: A Critical Regulatory Checkpoint

The conversion of the inactive hCAP18 pro-peptide into the active LL-37 is a critical, regulated step that requires enzymatic cleavage.6 This proteolytic activation is not a uniform process but is instead highly dependent on the cell type and local enzymatic environment, representing a key control point for cathelicidin activity. In neutrophils, the primary enzyme responsible for this cleavage is proteinase 3, a serine protease that is co-released from a different set of granules (azurophil granules) upon neutrophil activation and exocytosis (the process by which cells release molecules into the extracellular space).6 In epithelial tissues, such as the skin, a different set of serine proteases, primarily kallikrein 5 (also known as stratum corneum tryptic enzyme, SCTE) and kallikrein 7 (stratum corneum chymotryptic enzyme, SCCE), mediate the cleavage of hCAP18 to release LL-37.6

This tissue-specific processing is more than a simple on/off switch; it acts as a sophisticated functional tuning mechanism. The local protease milieu dictates not only whether LL-37 is produced but also whether alternative, functionally distinct fragments are generated. This is starkly illustrated in the contrasting pathologies of two inflammatory skin diseases. In rosacea, aberrant protease activity leads to the creation of pro-inflammatory peptide fragments that are different from LL-37 and drive the disease’s characteristic erythema.9 Conversely, in psoriatic lesions, the enzymatic environment favors the specific production of full-length LL-37, which has a distinct pathogenic mechanism.13 Furthermore, under normal physiological conditions, LL-37 can be further processed into smaller peptides like KR-20 and RK-31 in sweat, and the fragment KR-12 (residues 18–29) has been shown to retain antibacterial activity with reduced toxicity to human cells.5 This demonstrates that the biological outcome of CAMP gene expression is critically dependent on the downstream proteolytic landscape, which can be targeted therapeutically to modulate cathelicidin activity.

Structural and Physicochemical Properties

The active LL-37 peptide is defined by a unique set of structural and chemical features that are fundamental to its diverse biological functions.

Primary Structure: Its name is derived from its 37-amino-acid sequence, which begins with two leucine (L) residues: NH2-LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES-COOH.4
Physicochemical Nature: It is a relatively small peptide with a molecular weight of approximately 4.5 kDa. A key characteristic is its strong cationic nature, possessing a net positive charge of +6 at physiological pH. This charge arises from a surplus of basic amino acids, with 6 lysines and 5 arginines contributing 11 positive charges, partially offset by 3 glutamates and 2 aspartates bearing 5 negative charges.4
Secondary Structure and Amphipathicity: In aqueous solution, LL-37 is largely unstructured. However, upon encountering a membrane-mimetic environment, such as the negatively charged lipid bilayers of bacteria, it adopts a distinct α-helical conformation.5 This folding creates an amphipathic (or amphiphilic) structure, where the hydrophobic (water-repelling) amino acid residues are segregated to one face of the helix and the hydrophilic (water-attracting), positively charged residues are segregated to the opposite face.1 This spatial arrangement of charged and nonpolar regions is the essential structural basis for its ability to interact with and disrupt biological membranes, forming a curved helix-bend-helix motif that spans residues 2-31.5

III. Mechanisms of Action: A Multi-Target, Multi-Pathway Effector

LL-37 exerts its profound biological effects through two principal modes of action: direct antimicrobial activity against a wide range of pathogens and indirect immunomodulatory functions mediated by complex interactions with host cell receptors and signaling pathways.

Direct Antimicrobial and Anti-Biofilm Activities

The most fundamental function of LL-37 is its ability to directly kill invading microorganisms through a mechanism distinct from conventional antibiotics.

Electrostatic Interactions and Membrane Disruption: The primary antimicrobial mechanism is initiated by the strong electrostatic attraction between the positively charged LL-37 peptide and the net negative charge of microbial surfaces.6 These surfaces are rich in anionic molecules such as lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria, lipoteichoic acid (LTA) in the cell wall of Gram-positive bacteria, and anionic phospholipids in the cell membrane.7 Following this initial binding, the amphipathic α-helix inserts its hydrophobic face into the lipid bilayer. This disrupts the membrane’s integrity, leading to the formation of transmembrane pores or channels through models described as the “carpet” or “toroidal pore” mechanisms. This permeabilization causes a loss of ionic gradients, leakage of essential cellular contents, and ultimately, rapid cell lysis and death.15 This physical mode of action is less specific than the enzymatic targets of traditional antibiotics, making it more difficult for bacteria to evolve resistance.18
Broad Antimicrobial Spectrum: LL-37 exhibits potent activity against a diverse array of pathogens:

Bacteria: It is effective against numerous clinically relevant Gram-positive bacteria (e.g., Staphylococcus aureus) and Gram-negative bacteria (e.g., Pseudomonas aeruginosa, Escherichia coli), including multidrug-resistant (MDR) strains that are a major public health threat.15
Fungi: It possesses candidacidal (fungus-killing) activity against opportunistic fungi like Candida albicans. Its antifungal mechanism involves targeting the fungal cell wall and plasma membrane, disrupting calcium homeostasis, and inducing the production of damaging reactive oxygen species (ROS) within the fungal cell.20
Viruses: LL-37 demonstrates virucidal activity, particularly against enveloped viruses. It can directly disrupt the integrity of the viral envelope, a mechanism shown for viruses like Influenza A Virus (IAV), Human Immunodeficiency Virus (HIV), and Respiratory Syncytial Virus (RSV).24 Additionally, it can interfere with viral infection by blocking viral entry, either by binding directly to viral surface proteins (such as the S1 domain of the SARS-CoV-2 spike protein) or by masking host cell receptors like ACE2.7
Anti-Biofilm Activity: Biofilms are structured communities of microorganisms encased in a self-produced matrix, which are notoriously resistant to conventional antibiotics and host immune defenses. LL-37 is a potent anti-biofilm agent, capable of both preventing the initial attachment of bacteria to surfaces and eradicating mature, pre-formed biofilms.15 This capability is of significant therapeutic interest for treating chronic and device-related infections.

Immunomodulation via Receptor-Mediated Signaling

Beyond its direct microbicidal effects, LL-37 is a powerful signaling molecule that modulates the host immune response. It functions as a master regulator of how host cells perceive and respond to different types of threats, acting as a molecular “adjuvant” or co-factor that interprets the local microenvironment. For instance, when encountering bacterial endotoxin (LPS), it can neutralize it to dampen TLR4-mediated inflammation, signaling to “contain the toxin”.7 However, when it encounters self-DNA released from dead cells, it complexes with it to potently activate TLR9, signaling a “viral-like” threat that demands a massive interferon response.2 This ability to shape the quality and type of the immune response, not just its magnitude, explains its seemingly contradictory pro- and anti-inflammatory roles.

LL-37 as an “Alarmin”: Bridging Innate and Adaptive Immunity: Upon its release during infection or tissue damage, LL-37 acts as an “alarmin,” a key endogenous danger signal that mobilizes and directs the immune system.1 It is a potent chemoattractant (a chemical that attracts motile cells) for a variety of immune cells, including neutrophils, monocytes, mast cells, and T lymphocytes, recruiting them from the bloodstream to the site of injury or infection to initiate a coordinated response.4
Receptor Engagement and Signal Transduction: The diverse immunomodulatory effects of LL-37 are mediated through its interaction with a wide range of structurally unrelated cell surface receptors:

Formyl Peptide Receptor Like-1 (FPRL1/FPR2): This G-protein coupled receptor (GPCR) is a key receptor for LL-37 on phagocytic cells and lymphocytes. Its activation is a primary mechanism driving the chemotaxis of neutrophils, monocytes, and T cells.4 Beyond chemotaxis, FPRL1 signaling is also involved in LL-37-mediated angiogenesis and cancer cell migration.32
P2X7 Receptor: This ligand-gated ion channel, typically activated by extracellular ATP, is another important target of LL-37. Through P2X7, LL-37 can modulate critical cellular processes such as neutrophil apoptosis (programmed cell death), promote autophagy (a cellular recycling process important for clearing intracellular pathogens), and regulate the release of inflammatory cytokines from macrophages and keratinocytes.7
Epidermal Growth Factor Receptor (EGFR): LL-37 can indirectly activate, or “transactivate,” EGFR. This leads to the initiation of downstream signaling pathways that promote cell proliferation, survival, and migration, which is particularly important for epithelial wound healing but can also be co-opted by cancer cells to drive their growth.6
Toll-Like Receptors (TLRs): LL-37 has a complex, dualistic relationship with the TLR family of pattern recognition receptors. It can act as an anti-inflammatory agent by binding to and neutralizing LPS, thereby preventing its recognition by TLR4.7 In stark contrast, it can become a powerful pro-inflammatory driver by forming complexes with self-DNA and self-RNA. These complexes are then internalized and delivered to endosomal compartments where they potently activate TLR9 (for DNA) and TLR7/8 (for RNA), a central mechanism in the pathogenesis of autoimmune diseases like psoriasis and lupus.2
Other Receptors: LL-37 also engages with other receptors, including scavenger receptors, which facilitate the uptake of LL-37-nucleic acid complexes 37, and has been shown to interact with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) on the cell surface, a process linked to the induction of autophagy.6

Downstream Signaling Cascades: The engagement of these diverse receptors converges on a few core intracellular signaling pathways that translate the extracellular LL-37 signal into a cellular response:
PI3K/Akt Pathway: The Phosphoinositide 3-kinase (PI3K)/Akt pathway is a central regulator of cell survival, growth, and proliferation. LL-37 activates this pathway in various cell types to promote processes such as cancer cell migration and mast cell degranulation.32
MAPK Pathways: The Mitogen-Activated Protein Kinase (MAPK) cascades, including the p38 and ERK1/2 pathways, are critical for transducing extracellular stimuli into cellular responses like inflammation, proliferation, and differentiation. LL-37 is a well-established activator of p38 and ERK signaling in immune cells like monocytes and neutrophils, driving the production of inflammatory cytokines and promoting cell migration.32
NF-κB Pathway: The Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is a master regulator of genes involved in inflammation and immunity. The activation of various receptors by LL-37 can lead to the activation of NF-κB, contributing to its pro-inflammatory effects.32

IV. The Regenerative Potential of LL-37: Wound Healing and Angiogenesis

In addition to its role in combating infection, LL-37 is a potent mediator of tissue repair and regeneration. Its expression is strongly upregulated at the wound edge during the early phases of acute wound healing, where it contributes to multiple aspects of the repair process.41

Role in Cutaneous Wound Repair

LL-37 plays a vital role in orchestrating the complex process of skin wound healing. A primary function is its ability to promote re-epithelialization, which is the migration of keratinocytes to cover the wound surface and restore the epidermal barrier.8 It achieves this by stimulating both the proliferation and the directed migration of keratinocytes, effects that are mediated, in part, through the transactivation of the EGFR pathway.32 By accelerating this process, LL-37 helps to ensure rapid wound closure, which is critical for preventing infection and minimizing scarring.

Induction of Angiogenesis and Arteriogenesis

A hallmark of tissue repair is the formation of new blood vessels to supply oxygen and nutrients to the healing tissue, a process known as angiogenesis. LL-37 is a powerful pro-angiogenic factor, capable of stimulating the growth of new capillaries from pre-existing vessels.4

Preclinical Evidence: Robust preclinical data supports this function. In the in vivo chorioallantoic membrane (CAM) assay, a model for physiological angiogenesis, LL-37 induced significant, well-organized vessel growth.33 Furthermore, in a rabbit hind-limb ischemia model, which mimics pathological conditions of poor blood flow, LL-37 not only increased capillary density (angiogenesis) but also promoted the development of collateral circulation (arteriogenesis), leading to functionally significant improvements in blood flow to the ischemic limb.33
Mechanism of Action: The angiogenic activity of LL-37 is mediated by its direct action on endothelial cells, the cells that line blood vessels. It stimulates their proliferation and organization into tube-like structures. This effect is primarily transduced through the FPRL1 receptor on endothelial cells, which triggers downstream PI3K/Akt and MAPK signaling. Notably, this pro-angiogenic effect is independent of Vascular Endothelial Growth Factor (VEGF), a classical angiogenic factor, indicating that LL-37 activates a distinct pathway for vessel formation.33

Clinical Evidence in Chronic Wounds

The therapeutic potential of LL-37 is particularly relevant for chronic, hard-to-heal wounds, such as venous leg ulcers and diabetic foot ulcers, where the normal healing process is impaired and endogenous levels of LL-37 are often deficient.41

Venous Leg Ulcers (VLUs): A landmark randomized, double-blind, placebo-controlled clinical trial investigated the efficacy of topically applied synthetic LL-37 in patients with hard-to-heal VLUs.43 The results were highly encouraging, showing that treatment with LL-37 at concentrations of 0.5 mg/mL and 1.6 mg/mL was safe and resulted in healing rate constants that were approximately six-fold and three-fold higher than placebo, respectively.43 This led to a marked decrease in the mean ulcer area.
Diabetic Foot Ulcers (DFUs): In a separate randomized controlled trial focused on DFUs with mild infection, topical LL-37 cream was found to significantly enhance the rate of healing, as measured by a consistently greater increase in the granulation index (a marker of new tissue formation) over a four-week period compared to placebo.42 However, the study also noted that LL-37 did not significantly decrease the levels of pro-inflammatory cytokines or the number of aerobic bacteria in the wound, underscoring the complexity of its actions in the unique metabolic and inflammatory environment of a diabetic wound.42

A critical insight from these clinical studies is the existence of a biphasic or hormetic dose-response curve for LL-37’s regenerative effects. The VLU trial demonstrated that while lower doses were effective, a higher dose of 3.2 mg/mL was no better than placebo.43 This suggests a narrow therapeutic window. At optimal concentrations, LL-37 effectively promotes angiogenesis and cell migration. However, at excessive concentrations, its pro-inflammatory or cytotoxic properties may become dominant, counteracting the healing process.14 This observation is crucial for future therapeutic development, as it highlights that successful application will depend on maintaining a precise concentration at the target site, a challenge that may be addressed by controlled-release delivery systems.

V. The Pathogenic Face of LL-37: A Driver of Autoimmunity and Chronic Inflammation

While essential for acute defense, the dysregulation of LL-37 transforms it from a guardian of tissue integrity into a potent instigator of chronic inflammatory and autoimmune diseases. Its primary pathogenic role in these conditions is not as a simple inflammatory mediator but as a powerful adjuvant that makes the body’s own molecules appear foreign to the immune system. It facilitates a form of “pathogen mimicry,” tricking the immune system into mounting a sustained assault against self-components.

Psoriasis and Rosacea: Diseases of Cathelicidin Dysregulation

The skin provides the clearest examples of LL-37’s pathogenic potential.

Psoriasis: Psoriasis is a chronic autoimmune skin disease characterized by hyper-proliferative keratinocytes and severe inflammation. A key feature of psoriatic lesions is the massive and sustained overexpression of LL-37.9 The central pathogenic mechanism involves LL-37 binding to fragments of self-DNA and self-RNA that are released into the extracellular space by stressed or dying cells (such as neutrophils and keratinocytes).2 While self-nucleic acids are normally ignored by the immune system, the resulting LL-37-nucleic acid complexes become highly immunogenic. These complexes are taken up by plasmacytoid dendritic cells (pDCs), a specialized immune cell type, and delivered to endosomal compartments where they potently activate Toll-like receptor 9 (TLR9) and Toll-like receptors 7 and 8 (TLR7/8), respectively.13 This activation breaks immune tolerance and triggers a massive release of type I interferons (IFN-α), the hallmark of an anti-viral response. This interferon surge initiates a self-amplifying inflammatory cascade that drives the clinical manifestations of psoriasis.2
Rosacea: In contrast to the overexpression seen in psoriasis, the pathology of rosacea is driven by the aberrant processing of the hCAP18 precursor.13 In rosacea-affected skin, there is an increase in the activity of certain proteases that cleave hCAP18 into abnormal, shorter peptide fragments. These fragments, distinct from the full-length LL-37, are highly pro-inflammatory and are responsible for inducing the characteristic erythema (redness), telangiectasias (visible blood vessels), and inflammation of the disease.9 This highlights that both the quantity and the specific processed form of the cathelicidin peptide are critical determinants of its biological effect.

Systemic Lupus Erythematosus (SLE)

SLE is a systemic autoimmune disease characterized by widespread inflammation and the production of autoantibodies against nuclear components. Similar to psoriasis, LL-37 is a key player in its pathogenesis, contributing to the strong type I interferon signature that defines the disease.2 Neutrophils, which heavily infiltrate affected tissues in SLE, release large amounts of LL-37 and DNA during a process of cell death called NETosis.12 The LL-37 peptide complexes with this self-DNA, forming a potent autoantigen that stimulates pDCs to produce IFN-α, thereby perpetuating the systemic autoimmune cycle.2 Furthermore, LL-37 itself can become a direct target of the adaptive immune system; both autoantibodies against LL-37 and LL-37-specific T-cells are found in SLE patients, and their levels often correlate with disease activity.51

Atherosclerosis: Linking Inflammation and Cardiovascular Disease

Emerging evidence suggests that LL-37 may be a molecular link between the chronic inflammation seen in diseases like psoriasis and the increased risk of developing atherosclerosis (the hardening and narrowing of arteries). Patients with chronic inflammatory disorders have elevated systemic levels of LL-37.38 Mechanistic studies have shown that LL-37 can promote the uptake of low-density lipoprotein (LDL) and oxidized LDL by macrophages and endothelial cells, a critical initiating step in the formation of foam cells and the development of atherosclerotic plaques.38 This effect appears to be mediated by scavenger receptors and is a property specific to human and other primate cathelicidins, suggesting a unique and potentially detrimental role for LL-37 in lipid metabolism during chronic inflammatory states.38

VI. The Paradox of LL-37 in Oncology: Tumor Promoter and Suppressor

The role of LL-37 in cancer is one of its most complex and paradoxical aspects, as it can function as either a promoter or a suppressor of tumor growth depending on the specific cancer type.6 This dualistic behavior appears to be governed by the unique “receptor landscape” of each cancer cell type. Cancers that predominantly express pro-proliferative receptors responsive to LL-37 will interpret its signal as a command to grow, while those more susceptible to its membrane-disrupting properties or that express receptors linked to death pathways will undergo apoptosis.

Pro-Tumorigenic Mechanisms

In a number of malignancies, elevated expression of LL-37 is associated with tumor progression, metastasis, and poor clinical outcomes.10

Ovarian, Lung, and Breast Cancer: In these cancers, LL-37 functions as an autocrine or paracrine growth factor. It stimulates cancer cell proliferation, migration, and angiogenesis, thereby fueling tumor growth and invasion.10 The underlying mechanisms involve the transactivation of key receptor tyrosine kinases, such as the Epidermal Growth Factor Receptor (EGFR) and ErbB2, which in turn activate downstream pro-survival and pro-proliferative signaling pathways like MAPK/ERK.11 In lung cancer, LL-37 secreted by tumor-associated myeloid cells has also been shown to activate the Wnt/β-catenin signaling pathway in tumor cells, further promoting their growth.54
Recruitment of Pro-Tumor Cells: Beyond its direct effects on cancer cells, LL-37 can shape the tumor microenvironment to be more supportive of malignancy. For instance, it can chemoattract mesenchymal stromal cells to ovarian tumors or polarize macrophages toward a pro-tumorigenic M2 phenotype in prostate cancer, both of which contribute to tumor progression.32

Anti-Tumorigenic Mechanisms

In stark contrast, LL-37 expression is often lost or downregulated in other types of cancer, where it functions as a tumor suppressor.10

Colon and Gastric Cancer: In colorectal and gastric cancers, LL-37 and its synthetic derivatives (such as FK-16) have been shown to inhibit tumor cell proliferation and induce cell death.10 The primary mechanism is the induction of a caspase-independent form of apoptosis. This process involves the translocation of cell death-inducing factors like Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) from the mitochondria to the nucleus, leading to DNA fragmentation.10 LL-37 can also trigger autophagic cell death in these cancer cells.10
Hematologic Malignancies and Oral Squamous Cell Carcinoma: LL-37 also exhibits anti-cancer activity against various hematologic malignancies and oral squamous cell carcinoma, often through similar mechanisms involving the induction of apoptosis.53

This stark dichotomy underscores the critical importance of the cellular context in determining the ultimate biological effect of LL-37.

Condition & Context	Observed LL-37 Level & State	Primary Mechanism(s) of Action	Net Outcome
Acute Bacterial Infection	Inducibly Overexpressed	Direct membrane lysis of bacteria; Chemoattraction of neutrophils/monocytes.	Protective / Therapeutic
Chronic Wound (e.g., VLU)	Endogenously Low / Exogenously Applied	Promotes angiogenesis via FPRL1; Stimulates keratinocyte migration.	Therapeutic
Psoriasis	Chronically Overexpressed	Complexes with self-DNA/RNA, activating pDCs via TLR9/7 to produce Type I IFN.	Pathogenic
Systemic Lupus (SLE)	Overexpressed (esp. in NETs)	Acts as an autoantigen; Complexes with self-DNA to stimulate pDCs and IFN production.	Pathogenic
Colon Cancer	Downregulated / Lost	Induces caspase-independent apoptosis and autophagy in tumor cells.	Anti-Tumorigenic
Ovarian / Lung Cancer	Overexpressed	Acts as a growth factor; Activates EGFR/ErbB2 pathways; Promotes angiogenesis.	Pro-Tumorigenic
Atherosclerosis	Elevated in Inflammatory Plaques	Promotes LDL uptake into macrophages and endothelial cells via scavenger receptors.	Pathogenic

VII. Therapeutic Development: Promise, Challenges, and Innovations

The potent and multifaceted biological activities of LL-37 have made it an attractive candidate for therapeutic development, particularly in the fields of infectious disease and wound healing. However, its translation from the laboratory to the clinic is hampered by significant challenges inherent to its pleiotropic nature.

Potential as a Novel Antibiotic

In an era defined by the escalating crisis of antimicrobial resistance, LL-37 and its derivatives represent a promising alternative to conventional antibiotics.15 Its rapid, membrane-disrupting mechanism of action is effective against a broad range of MDR pathogens, including methicillin-resistant

Staphylococcus aureus (MRSA) and colistin-resistant Gram-negative bacteria.19 Its ability to eradicate biofilms further enhances its appeal for treating chronic and device-associated infections, which are often intractable to standard antibiotic therapy.19

Hurdles to Clinical Translation

Despite its clear potential, the development of native LL-37 as a systemic or topical therapeutic is constrained by several major obstacles:

Cytotoxicity: The concentrations of LL-37 required for effective bactericidal activity often overlap with concentrations that are toxic to host cells. This can lead to undesirable side effects such as hemolysis (rupture of red blood cells) and damage to other mammalian cells, limiting its therapeutic window.7 Studies have also shown that LL-37 can selectively permeabilize apoptotic host cells, which could lead to the release of intracellular contents and potentially exacerbate inflammation.46
Proteolytic Instability: As a peptide, LL-37 is susceptible to degradation by proteases present in biological fluids like serum and wound exudate. Proteases produced by pathogenic bacteria, such as the elastase from P. aeruginosa, can also rapidly inactivate the peptide, reducing its efficacy at the site of infection.15
High Manufacturing Cost: The solid-phase chemical synthesis of a 37-amino-acid peptide is a complex and costly process. The expense of producing pharmaceutical-grade LL-37 at scale is a significant barrier to its commercial viability and widespread clinical use.15
Development of Bacterial Resistance: While initially considered less prone to resistance, it is now clear that bacteria can develop resistance to LL-37, particularly following prolonged exposure to sub-lethal concentrations. Furthermore, mechanisms of resistance to cationic peptides can sometimes confer cross-resistance to last-resort antibiotics like colistin, which shares a similar membrane-targeting mechanism.15

Overcoming Limitations

The future of LL-37-based therapy likely lies not with the native peptide itself, but with sophisticated bioengineering approaches designed to optimize its properties. The goal is to create therapeutic platforms that decouple its beneficial activities (e.g., targeted antimicrobial action, regeneration) from its detrimental ones (e.g., cytotoxicity, systemic inflammation) by precisely controlling its structure and delivery.

Development of Synthetic Derivatives and Fragments: A major focus of research is the rational design of synthetic analogs and shorter fragments of LL-37. By modifying the amino acid sequence, researchers aim to create peptides with an improved therapeutic index (a measure of a drug’s safety, comparing its therapeutic effect to its toxic effect). For example, the 12-amino-acid fragment KR-12 retains antibacterial activity but shows reduced toxicity.5 Other derivatives, such as P60.4Ac and SAAP-148, have been engineered for enhanced antimicrobial potency and improved stability in biological fluids, overcoming a key limitation of the parent peptide.19
Advanced Delivery Systems: To address issues of instability and toxicity, researchers are developing advanced delivery systems to encapsulate LL-37. These platforms can protect the peptide from proteolytic degradation, provide sustained and controlled release at the target site, and reduce systemic exposure. Promising strategies include:

Nanoparticles: Encapsulation in biodegradable polymeric nanoparticles (e.g., made from PLGA or chitosan) or lipid-based nanoparticles can improve stability and bioavailability.63
Hydrogels: Formulating LL-37 into hydrogels creates a moist environment conducive to wound healing while providing a matrix for sustained peptide release directly at the wound site.65 Some advanced systems are designed to release their LL-37 payload in response to local environmental cues, such as the presence of reactive oxygen species in a wound bed.66

These integrated approaches, combining a structurally optimized peptide payload with a smart delivery vehicle, represent the most viable path toward harnessing the therapeutic power of LL-37 safely and effectively.

VIII. Conclusion

The human cathelicidin LL-37 is a molecule of profound biological complexity and significance. It stands as a central pillar of innate immunity, wielding a potent arsenal of direct antimicrobial weapons while simultaneously acting as a master conductor of the host’s inflammatory and regenerative responses. This review has detailed the striking dichotomy that defines its character: it is both an essential protector and a potential pathogen. The context of its action—determined by its concentration, local enzymatic environment, and the specific receptor landscape of target cells—is the ultimate arbiter of its function, deciding whether it heals a wound or fuels an autoimmune fire, suppresses a tumor or promotes its growth.

The therapeutic potential of LL-37 is undeniable. In an age of dwindling antibiotic efficacy, its broad-spectrum, anti-biofilm activity offers a new paradigm for treating infections caused by multidrug-resistant organisms. Its powerful pro-regenerative capabilities have been validated in clinical trials for chronic wounds, offering hope for conditions that currently have few effective treatments. However, the path to widespread clinical use is obstructed by formidable challenges. The inherent cytotoxicity of the peptide at therapeutic doses, its susceptibility to degradation, the high cost of manufacturing, and the potential for bacterial resistance are significant hurdles that must be overcome.

The future of LL-37-based therapeutics will be driven by innovation. The focus of research is rightly shifting from the native peptide to the development of next-generation derivatives and intelligent delivery systems. Through rational peptide design, it may be possible to engineer molecules that retain the desired antimicrobial or regenerative functions while shedding the unwanted toxicity and pro-inflammatory baggage. Concurrently, advanced delivery platforms such as responsive hydrogels and targeted nanoparticles promise to deliver these optimized peptides precisely where they are needed, maintaining concentrations within the narrow therapeutic window and minimizing off-target effects.

Looking forward, several key areas warrant further investigation. More robust, large-scale clinical trials are essential to definitively establish the efficacy and safety of LL-37 and its derivatives in various clinical settings. Continued exploration of the fundamental biology of LL-37, particularly its interaction with the vast array of host receptors and signaling pathways, will uncover new opportunities for therapeutic intervention. Finally, strategies aimed at modulating the expression and processing of endogenous LL-37, perhaps through nutritional interventions like vitamin D or the targeted inhibition of specific proteases, may offer a complementary approach to exogenous administration, allowing for a more nuanced and physiological way to harness the power of the body’s own cathelicidin. Ultimately, successfully translating the promise of LL-37 into a clinical reality will require a multidisciplinary effort, combining insights from immunology, molecular biology, and bioengineering to tame this powerful “double-edged sword” for therapeutic benefit.