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Kallikrein related peptidase 5 (KLK5) is the enzyme at the centre of three major skin disease mechanisms and one of the most underappreciated regulatory molecules in clinical skin biology. In healthy skin, it does exactly what the epidermis needs: it initiates the controlled degradation of corneodesmosomal adhesion proteins in the superficial stratum corneum, enabling desquamation – the shedding of dead corneocytes – while simultaneously processing the inactive LL-37 precursor hCAP18 into active antimicrobial peptide and initiating the broader KLK protease cascade. Two regulatory controls keep it precisely localised to the uppermost corneal layers: the serine protease inhibitor LEKTI, encoded by SPINK5, and the acidic pH gradient of the skin surface, which reduces KLK5 activity below the tight junctions where desquamation must not occur.

When either control fails – KLK5 becomes the engine of destruction. In rosacea, excess KLK5 drives the entire inflammatory cascade through LL-37 overproduction. In atopic dermatitis, alkaline pH removes the pH brake and allows excess KLK5 to degrade filaggrin and corneodesmosomal proteins, compounding the barrier deficit. In Netherton syndrome, the complete genetic absence of LEKTI produces unrestrained KLK5 activity that destroys the barrier catastrophically from birth. The molecule is not pathological. The loss of its regulatory environment is.

The stratum corneum is not simply a passive physical barrier that sits on top of the epidermis. It is a continuously renewing structure that sheds its outermost corneocytes through a tightly regulated enzymatic process while simultaneously maintaining the structural integrity of the layers beneath. KLK5 is the protease at the centre of that process – and understanding what it does under control, and what happens when control is lost, explains a remarkable proportion of the pathological mechanisms in inflammatory skin disease.

KLK5 as the master initiating protease

KLK5 is a kallikrein-related peptidase – a family of fifteen serine proteases expressed predominantly in epithelia, with skin expressing the highest concentration and diversity of the family. Within that family, KLK5 occupies a uniquely central position: it is the only member capable of robust autoactivation – cleaving its own zymogen precursor form to generate active enzyme without requiring another upstream protease. This self-initiating capacity makes KLK5 the master initiating enzyme of the epidermal KLK cascade: it activates itself, then activates KLK7 (a chymotrypsin-like partner protease with complementary corneodesmosomal substrate specificity) and KLK14, which further amplifies the proteolytic signal. sciencedirect

The cascade architecture means that KLK5 is not merely one among several equivalent proteases. It is the switch. When KLK5 activates, it triggers a self-amplifying proteolytic programme that processes multiple substrates in parallel. When KLK5 is inhibited, the entire downstream cascade stalls – which is why KLK5 is the therapeutic target of choice in conditions where the cascade is pathologically overactivated, and why its dysregulation produces such wide-ranging consequences when the regulatory controls fail. ^[3]

Normal function: controlled desquamation and the corneodesmosomal substrates

In healthy stratum corneum, KLK5 activity is confined to the uppermost corneocyte layers by the pH gradient and LEKTI inhibition described below. Within those superficial layers, KLK5 performs two physiologically essential functions.

Corneodesmosomal cleavage. Corneodesmosomes are the modified intercellular junctions that hold adjacent corneocytes together throughout the stratum corneum. Normal desquamation requires their progressive degradation from the outer corneal surface inward – shedding the outermost corneocytes while maintaining adhesion in the deeper layers until those cells mature to the surface. KLK5 achieves this by cleaving two primary corneodesmosomal components: desmoglein-1 (Dsg1) and corneodesmosin (CDSN), the extracellular adhesion proteins spanning the desmosomal junction. KLK7 cleaves desmocollin-1 (Dsc1) complementarily. Together, these two proteases dismantle the corneodesmosomal scaffold layer by layer, enabling the physiological skin surface renewal that healthy skin achieves imperceptibly every two to four weeks. ^[2]

Profilaggrin processing. KLK5 and KLK7 both contribute to processing profilaggrin into its functional filaggrin monomers within the granular layer. This is a separate substrate from the corneodesmosomal targets – and it establishes a direct connection between KLK5 activity and filaggrin availability. In conditions where KLK5 dysregulation produces excess protease activity, filaggrin is not merely failing to be produced (as in FLG null mutations); it is being actively degraded by uncontrolled KLK5 activity. The barrier consequences compound accordingly. ^[7]

hCAP18 → LL-37 processing. KLK5 is the primary enzyme responsible for cleaving the inactive cathelicidin precursor hCAP18 to generate active LL-37 at the skin surface. This processing function positions KLK5 at the intersection of two distinct biological systems – epidermal homeostasis and innate antimicrobial defence – making it the regulatory node that co-ordinates both simultaneously. The pH dependence of KLK5 therefore regulates not only desquamation but the rate of LL-37 production at the skin surface. ^[9]

The dual control system: LEKTI and pH

KLK5 activity in healthy skin is held within precisely the right spatial and quantitative range by two overlapping control mechanisms that operate in complementary ways.

LEKTI – the protease inhibitor encoded by SPINK5. LEKTI (Lympho-Epithelial Kazal-type Trypsin Inhibitor) is a multi-domain serine protease inhibitor produced by keratinocytes and secreted into the intercellular spaces of the stratum corneum. Its primary target is KLK5 – it inhibits KLK5 with higher affinity than any other KLK family member – and it secondarily inhibits KLK7, KLK6, KLK13, and KLK14. LEKTI functions as a stoichiometric inhibitor: it binds KLK5 and physically blocks its catalytic site, with inhibition holding as long as LEKTI concentration is adequate and the pH conditions maintain the LEKTI-KLK5 binding affinity. ^[8]

pH gradient – the spatial control mechanism. The second control is elegantly architectural. LEKTI’s inhibitory affinity for KLK5 is pH-dependent: it binds KLK5 tightly at the alkaline pH of the deeper stratum corneum (~pH 7.0, near the stratum granulosum junction) and releases KLK5 progressively as pH decreases toward the acidic skin surface (~pH 4.5–5.5). This pH-dependent release means that KLK5 activity is spatially restricted by the natural pH gradient of the stratum corneum – inhibited in the deeper layers where corneodesmosomes must remain intact to maintain structural integrity, and active only in the superficial layers where desquamation is appropriate. KLK5 activity is therefore not simply switched on or off. It is precisely positioned within the stratum corneum by a pH-gradient that functions as a spatial gating mechanism. ^[3]

The clinical significance of this architecture is profound. Any condition or intervention that raises the skin surface pH – alkaline cleansers, hard water mineral deposition, barrier dysfunction – disrupts the spatial gating. KLK5 activity expands into deeper corneal layers where it should not be active. Desquamation accelerates beyond the physiological rate. hCAP18 cleavage and LL-37 production increase. Filaggrin processing is disrupted. Everything downstream of KLK5 dysregulates together, from a single upstream cause: pH elevation. ^[6]

Netherton syndrome – the genetic proof-of-concept

Netherton syndrome (NS) is a rare autosomal recessive genodermatosis caused by loss-of-function mutations in SPINK5 – the gene encoding LEKTI. In its severe form, it is one of the most dramatic demonstrations in all of dermatology of what a single enzyme does when its primary inhibitor is absent.

Without functional LEKTI, KLK5 activity in the stratum corneum is unrestrained. The consequences unfold in a precise mechanistic sequence that the SPINK5 knockout mouse model has mapped in molecular detail, with the 2015 PLoS Genetics study (PMC for KLK5 inactivation reversal) providing the most definitive experimental evidence: when KLK5 was genetically deleted in LEKTI-deficient mice, neonatal lethality was rescued, the severe skin barrier defect reversed, epidermal architecture restored, and filaggrin expression normalised. The experiment confirmed that KLK5 hyperactivity – not LEKTI absence itself – is the proximate cause of the barrier destruction in NS. ^[4]

The sequence of pathological events from uncontrolled KLK5 is:

1. Corneodesmosomal degradation in all corneal layers simultaneously – not just the superficial layers where it is physiologically appropriate – producing premature corneocyte detachment, the ichthyosis linearis circumflexa (double-edged migratory scaly plaques) and constant skin shedding characteristic of the condition ^[10]

2. Filaggrin degradation – both direct KLK5 cleavage of filaggrin monomers and disrupted profilaggrin processing – producing a profound barrier lipid deficit and natural moisturising factor (NMF) deficiency ^[4]

3. Excess LL-37 generation – uncontrolled hCAP18 cleavage producing sustained LL-37 overproduction with the full mast cell degranulation and inflammatory cascade consequences described in the LL-37 entity ^[6]

4. Allergen penetration through the destroyed barrier – producing the hyperallergic, elevated IgE, eosinophilic phenotype of NS; these patients have allergies to essentially everything their skin contacts ^[5]

5. IL-17 and TNF-α elevation – LEKTI deficiency disrupts cytokine regulation directly, with elevated IL-17A and TNF-α reported, which further stimulates KLK5 expression and sustains the inflammatory loop ^[5]

Netherton syndrome is KLK5 dysregulation taken to its logical extreme. The condition is not merely an illustration of what can go wrong – it is the genetic experiment that proved KLK5 is the causal driver of the corneodesmosomal and barrier destruction, not a bystander in LEKTI deficiency. ^[4]

KLK5 in rosacea

Rosacea provides the most clinically common example of KLK5 dysregulation – and the most precisely characterised inflammatory cascade downstream of a single serine protease in dermatology. The mechanism is covered in full in the LL-37 entity; the KLK5-specific dimensions are:

KLK5 levels are elevated in rosacea facial skin, with a direct correlation established between serine protease activity (SPA) levels measured by tape-stripping and rosacea disease severity. In a multicentre study of 55 adults with papulopustular rosacea, high baseline SPA was associated with more severe inflammatory manifestations and greater vascular involvement. ^[9]

The pathological KLK5 overactivity in rosacea is not fully explained by pH elevation alone, though acid mantle disruption contributes. Multiple rosacea triggers – UV radiation, heat, Demodex mite serine proteases, certain foods, emotional stress – activate KLK5 expression or activity through pattern recognition and inflammatory signalling pathways independently of pH. The result is KLK5 activity that exceeds what the acid mantle and LEKTI levels can contain, even when those regulatory controls are functioning. ^[9]

The aberrant processing fragments deserve specific mention. In rosacea, excess KLK5 does not simply generate more LL-37. It generates LL-37 processing variants – N-terminal and internal fragments not present in healthy skin – that activate TLR2 and drive inflammatory signalling through pathways that are not identical to intact LL-37. These variants are a product of dysregulated KLK5 kinetics: when KLK5 is operating at the correct rate with adequate substrate, hCAP18 cleavage produces the standard 37 amino acid product. When KLK5 is hyperactivated and substrate turnover is accelerated, off-pathway cleavage products accumulate. The aberrant fragments are therefore not just a consequence of excess LL-37 production – they are a signature of KLK5 dysregulation itself. ^[9]

KLK5 in atopic dermatitis

AD does not produce KLK5 hyperactivation on the scale seen in rosacea or NS. But the pH mechanism operates consistently: the alkaline skin surface of AD-affected skin (elevated from the pH ~4.5–5.5 of healthy skin toward pH ~6.0–7.0 in moderate-severe presentations) shifts KLK5 activity beyond the LEKTI-controlled range in the deeper stratum corneum. The result is a KLK5 activity level that, while not dramatically elevated, is active in skin layers where the structural integrity of corneodesmosomes and filaggrin should be protected. ^[6]

This mechanism contributes to the accelerated barrier protein degradation in AD: the filaggrin that is already being inadequately produced (due to FLG mutations or IL-4/ IL-13-driven suppression) is also being more aggressively degraded by sub-pathologically-elevated but still dysregulated KLK5 activity. The corneodesmosomal architecture of AD skin is similarly compromised by this mechanism – contributing to the impaired desquamation and abnormal skin surface texture characteristic of atopic presentations. ^[7]

Zingkou et. al (2025) found that KLK5 deletion in a CDSN-nEDD congenital ichthyosis mouse model – suggesting that KLK5’s LL-37 processing function provides protective AMP activity in barrier-diseased skin, with probable relevance to AD where similar KLK5 dysregulation operates. This nuance matters: in AD, the goal is not KLK5 suppression (which would reduce LL-37 production further, worsening the AMP deficit), but pH restoration that returns KLK5 to its physiologically appropriate spatial restriction. ^[11]

KLK5 in psoriasis

In psoriasis, the IL-17A-dominated Th17 environment drives upregulation of multiple KLK family members, including KLK5. Elevated KLK5 in psoriatic plaques contributes to the accelerated keratinocyte turnover and abnormal desquamation characteristic of the condition – the thick, silvery scale of psoriasis reflects, in part, dysregulated corneodesmosomal remodelling driven by excess protease activity rather than normal corneocyte maturation. ^[2]

KLK5’s role here is part of the broader protease dysregulation in psoriasis rather than the primary pathological driver (as it is in rosacea and NS), but its elevation means that the KLK cascade is contributing to both the abnormal barrier turnover and the excess LL-37 production that participates in the IL-17A/LL-37 amplification loop of psoriatic inflammation.

Emerging therapeutic targeting of KLK5

Three therapeutic approaches to direct KLK5 inhibition are at various stages of development, all conceptually grounded in the Netherton syndrome genetic proof-of-concept:

Dual KLK5/KLK7 antibody inhibition. A 2022 Science Translational Medicine paper established that dual inhibitory antibodies targeting both KLK5 and KLK7 simultaneously produced meaningful barrier restoration in NS models and showed translational potential for severe AD. The rationale for dual inhibition rather than KLK5 alone is the complementary substrate specificity: KLK5 and KLK7 together cleave the full range of corneodesmosomal adhesion proteins, so inhibiting only one allows the other to continue degrading its substrates. ^[1] Preclinical evidence for the KLK/NS therapeutic axis is reviewed in Zingkou et al. (2026). ^[10]

LEKTI-grafted synthetic inhibitors. Mah et. al (2025) described a sunflower trypsin inhibitor scaffold grafted with LEKTI functional domains – a protease-stable synthetic inhibitor designed to replicate LEKTI’s KLK5-inhibitory activity. The concept is topical LEKTI replacement: delivering an exogenous KLK5 inhibitor that restores the regulatory control absent in NS or dysregulated in rosacea without the need for gene therapy or systemic biologics. ^[6]

KLK5 inhibition as a rosacea-specific target. SE1003 (a small-molecule KLK5 inhibitor) has been investigated in rosacea clinical studies alongside azelaic acid and doxycycline – the two existing agents with confirmed KLK5-inhibitory mechanisms. Azelaic acid suppresses KLK5 mRNA and protein expression in keratinocytes. Doxycycline at sub-antimicrobial concentrations inhibits the serine protease activity of KLK5 at the protein level. Both are currently the only clinically available KLK5-targeting interventions in routine practice. ^[9]