Lacritin: The Tear Peptide for Dry Eye
Ocular Peptides
204 patients enrolled
The first-in-human trial of Lacripep, a synthetic fragment of lacritin, enrolled 204 Sjogren's syndrome patients and showed significant reductions in corneal damage and burning within two weeks.
Tauber et al., Cornea, 2023
Tauber et al., Cornea, 2023
View as imageIn 2001, Gordon Laurie's laboratory at the University of Virginia identified a protein in human tears that no one had characterized before. They named it lacritin, from the Latin lacrima (tear), and showed it was highly expressed in the lacrimal gland, the organ that produces the aqueous layer of the tear film. Recombinant lacritin stimulated secretion from lacrimal acinar cells that had otherwise lost their secretory function in culture, promoted ductal cell proliferation, and triggered intracellular calcium signaling.[1] No other tear protein shared these properties.
In the two decades since, lacritin has been linked to dry eye disease through a straightforward mechanism: people with dry eye have less of it in their tears, and restoring it appears to restore tear production and surface healing. A synthetic fragment called Lacripep completed its first-in-human trial in 2022, showing statistically significant improvements in both corneal damage and symptom scores in Sjogren's syndrome patients within 14 days.[2] This article covers lacritin's biology, its role in dry eye disease, and the clinical evidence to date. For how peptides protect the cornea from infection, see Antimicrobial Peptides and Corneal Infections: Protecting Your Eyes. For another ocular healing peptide, see Thymosin Beta-4 for Corneal Healing: Eye Injury Research.
Key Takeaways
- Lacritin was discovered in 2001 by Sanghi et al. as a novel secretion-enhancing glycoprotein highly expressed in the human lacrimal gland, with no known homologs sharing its prosecretory function
- The protein binds syndecan-1 only after heparanase removes heparan sulfate chains, creating an enzyme-regulated "off-on" switch that restricts lacritin activity to specific cellular contexts (Ma et al., 2006; Dias-Teixeira et al., 2020)
- Tears from Sjogren's syndrome patients contain significantly less lacritin; topical lacritin increased tear secretion by 46% in Aire knockout mice and reduced corneal surface damage (Vijmasi et al., 2014)
- The first-in-human trial of Lacripep (19 amino acid C-terminal fragment) in 204 Sjogren's patients showed a -0.4 reduction in inferior corneal staining (p=0.0055) and -14.5 point reduction in burning/stinging (p=0.0024) at two weeks (Tauber et al., 2023)
- Lacritin triggers cell survival through FOXO-dependent autophagy and mitochondrial fusion, distinguishing it from existing dry eye therapies that target downstream inflammation rather than the underlying secretory deficit
- A 2025 glycoproteomic analysis identified 19 O-glycosites on lacritin and detected two spliceoforms for the first time, revealing previously unknown structural complexity (Chang et al., 2025)
Discovery and structure of lacritin
Sanghi et al. (2001) identified lacritin through a differential display screen of the human lacrimal gland, searching for genes expressed in lacrimal tissue but not in other organs. The LACRT gene encodes a 138-amino-acid secreted glycoprotein, consisting of five exons with no alternative splicing detected at the time. Lacritin mRNA was most abundant in the lacrimal gland, with moderate expression in major and minor salivary glands and low expression in thyroid.[1]
Ma et al. (2008) published a detailed molecular profile of lacritin in their "Focus on Molecules" review, describing a 12.3 kDa protein that is both glycosylated and proteolytically processed. The N-terminal region mediates cell targeting, while the C-terminal amphipathic alpha-helix (roughly the last 19 amino acids) is responsible for the prosecretory and mitogenic activity.[3] This C-terminal fragment later became the basis for Lacripep, the synthetic therapeutic candidate.
Chang et al. (2025) applied modern glycoproteomics to lacritin for the first time, identifying 19 O-glycosylation sites bearing diverse glycan structures. The O-glycosylation renders the protein backbone rigid and extended rather than flexible, which has implications for how lacritin interacts with its receptor. The study also detected protein-level evidence of two lacritin spliceoforms by mass spectrometry, contradicting the original finding of no alternative splicing and suggesting additional regulatory complexity in lacritin biology.[4]
The glycosylation findings have practical implications for therapeutic development. Lacripep, the synthetic 19-amino-acid fragment, lacks glycosylation because it is produced by chemical synthesis rather than recombinant expression. If O-glycosylation affects lacritin's stability, binding affinity, or tissue distribution, the synthetic fragment may behave differently from the endogenous protein in ways that are not yet characterized. Conversely, if the C-terminal active region is not glycosylated (the 19 O-glycosites may cluster in the N-terminal and central regions), Lacripep may faithfully reproduce the key biological activity despite lacking the full protein's sugar coating.
Why dry eye disease needs new approaches
Dry eye disease affects an estimated 344 million people globally, making it one of the most common reasons for ophthalmology visits. The condition ranges from mild irritation to severe, vision-threatening corneal damage. Current treatments fall into three categories: artificial tears (temporary lubrication that does not address the underlying cause), anti-inflammatory agents like cyclosporine A (Restasis) and lifitegrast (Xiidra) that suppress the immune-mediated inflammation driving surface damage, and secretagogues like diquafosol that stimulate mucin and fluid secretion from conjunctival goblet cells.
None of these approaches addresses the lacrimal gland dysfunction that underlies aqueous-deficient dry eye. Sjogren's syndrome, the autoimmune condition that destroys lacrimal and salivary glands, affects 1-4 million Americans and has no disease-modifying therapy for the glandular destruction itself. Even in milder forms of dry eye, the lacrimal gland's secretory capacity declines with age and inflammation, and no existing drug restores it. This is the gap lacritin was identified to fill: a prosecretory molecule that could restart tear production from the lacrimal gland itself.
The syndecan-1-heparanase binding mechanism
Lacritin does not bind its receptor constitutively. It requires an enzymatic "unlock" step, which gives the system a built-in selectivity mechanism.
The receptor is syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan expressed on epithelial cells. Under normal conditions, syndecan-1's core protein is heavily decorated with heparan sulfate (HS) chains that block lacritin from accessing its binding site. Lacritin can only bind after the enzyme heparanase cleaves away the HS chains, exposing a region in syndecan-1's N-terminal domain.[5]
Dias-Teixeira et al. (2020) reviewed the full lacritin-syndecan-1-heparanase axis, describing it as a novel "on-switch" that restricts lacritin signaling to specific contexts: cells must be expressing both syndecan-1 and active heparanase for lacritin to bind and signal. This restricts lacritin's activity to epithelial surfaces (which express syndecan-1) that are undergoing active tissue remodeling (which activates heparanase), making the system self-targeting to damaged or inflamed mucosal surfaces.[5]
Once bound, lacritin triggers intracellular signaling through a pertussis toxin-sensitive G-protein coupled pathway. This leads to FOXO-dependent transcription, transient acceleration of autophagy (within 1-10 minutes), and mitochondrial fusion. The autophagy component clears damaged cellular components, while mitochondrial fusion restores oxidative phosphorylation capacity in epithelial cells that have been stressed by inflammation or desiccation.[5]
This mechanism distinguishes lacritin from every existing dry eye therapy. Current treatments (cyclosporine, lifitegrast, artificial tears) address downstream consequences of dry eye: inflammation, symptom relief, or temporary lubrication. Lacritin acts on the underlying secretory machinery of the lacrimal and ocular surface epithelial cells themselves.
Autophagy, mitochondrial fusion, and cell survival
The downstream signaling from lacritin-syndecan-1 binding is unusual among tear proteins. Lacritin triggers a transient burst of autophagy, the cellular self-cleaning process that degrades damaged organelles and misfolded proteins. In ocular surface epithelial cells stressed by desiccation or inflammation, this autophagy clears accumulated cellular damage and restores normal function.
Critically, lacritin also promotes mitochondrial fusion. Mitochondria in stressed epithelial cells become fragmented, reducing their capacity for oxidative phosphorylation and ATP production. Lacritin reverses this fragmentation by promoting fusion of mitochondrial networks, restoring energy production capacity. This dual action, clearing damage through autophagy while rebuilding energy infrastructure through mitochondrial fusion, explains why lacritin has both prosurvival and prosecretory effects: a cell that has been "cleaned up" and re-energized can resume its normal secretory function.
The autophagy response is rapid (within 1-10 minutes of lacritin binding) and transient (returning to baseline within 24 hours), suggesting it acts as a reset signal rather than a chronic stimulus. This temporal profile is consistent with lacritin functioning as a homeostatic regulator: it corrects dysfunction when present, then allows the cell to return to normal operation.
Lacritin deficiency in dry eye disease
Karnati et al. (2013) published a comprehensive review of lacritin's role in the tear proteome. They documented that lacritin is consistently reduced in the tears of patients with multiple forms of dry eye disease, including Sjogren's syndrome, non-Sjogren's aqueous-deficient dry eye, and meibomian gland dysfunction. The reduction is not simply a consequence of reduced tear volume; lacritin is disproportionately depleted relative to other tear proteins.[6]
The deficiency appears functional rather than coincidental. The tear proteome contains over 1,500 identified proteins. Of these, lacritin is the only one with documented prosecretory activity, the ability to stimulate tear production from lacrimal acinar cells. Its depletion in dry eye patients correlates with their primary complaint: insufficient tear production.
Karnati et al. proposed lacritin as a "natural replacement therapy" for dry eye, arguing that replacing a depleted endogenous protein is a fundamentally different approach from suppressing inflammation (cyclosporine) or blocking T cell migration (lifitegrast). The analogy they drew was to insulin replacement in diabetes: restoring a deficient signaling molecule rather than treating its downstream consequences.[6]
Preclinical evidence: the animal model data
Vijmasi et al. (2014) conducted the key preclinical study that established lacritin's therapeutic potential. Using Aire knockout mice (which develop autoimmune destruction of the lacrimal gland, modeling Sjogren's syndrome), they tested topical lacritin administration three times daily for 21 days.[7]
The results were striking. Lacritin-treated eyes showed a 46% increase in tear secretion compared to vehicle-treated contralateral eyes. Lissamine green staining scores (a measure of ocular surface damage) decreased significantly in the lacritin group. Histological examination showed reduced focal infiltration of CD4+ T cells in the lacrimal glands of lacritin-treated animals, suggesting the peptide had both prosecretory and anti-inflammatory effects.[7]
The study also confirmed that lacritin was significantly reduced in the tears of human Sjogren's syndrome patients, establishing both the deficiency and the therapeutic response in the same publication. The dual finding, deficiency in disease plus restoration of function upon replacement, provided the rationale for clinical development.
The Aire knockout model is particularly relevant because it recapitulates key features of human Sjogren's syndrome: autoimmune-mediated lymphocytic infiltration of the lacrimal gland, progressive glandular destruction, and resultant aqueous tear deficiency. The fact that topical lacritin, applied to the ocular surface rather than directly to the lacrimal gland, produced both increased tear secretion and reduced glandular inflammation suggests the peptide acts through a signaling cascade that reaches the gland from the surface, possibly through neural reflex pathways or through lacritin's direct uptake into lacrimal ductular epithelium.
First-in-human trial: Lacripep in Sjogren's syndrome
Tauber et al. (2023) published the results of the first-in-human clinical trial of Lacripep, a synthetic 19-amino-acid peptide corresponding to lacritin's active C-terminal fragment, in the journal Cornea.[2]
The trial enrolled 204 patients with primary Sjogren's syndrome-associated ocular surface disease, randomized to receive vehicle, 22 micromolar Lacripep, or 44 micromolar Lacripep three times daily for 28 days. A 14-day run-in preceded treatment, and a 14-day washout followed.
At two weeks, the 0.005% Lacripep group showed a -0.4 reduction in inferior corneal staining (the Oxford grading system, p=0.0055 versus vehicle) and a -14.5 point reduction in burning and stinging complaints (p=0.0024 versus vehicle). Safety was favorable: mild irritation occurred in less than 3% of Lacripep-treated patients, with no serious adverse events.[2]
The speed of response was notable. Two weeks to statistically significant improvement in both signs and symptoms compares favorably to cyclosporine ophthalmic emulsion (Restasis), which typically requires 3-6 months for full effect. The trial was not designed or powered for a head-to-head comparison, and the 28-day treatment period was too short to assess durability of response. The results established safety, tolerability, and preliminary efficacy signals for further development.
Several limitations are worth noting. Sjogren's syndrome represents the most severe end of the dry eye spectrum, and a peptide effective in Sjogren's may or may not be effective in the more common evaporative dry eye or age-related dry eye. The trial used two dose levels but did not identify a clear dose-response relationship, making it unclear whether higher or lower doses might be more effective. And the study relied on a run-in period that could have introduced regression-to-the-mean effects in the vehicle group.
The ocular surface peptide landscape
Lacritin operates within a broader ecosystem of peptides active at the ocular surface. Ting et al. (2022) reviewed host defense peptides at the ocular surface, documenting the roles of defensins, cathelicidin (LL-37), and other antimicrobial peptides in maintaining corneal health and preventing infection.[8] These peptides protect against microbial invasion, but none shares lacritin's prosecretory function.
Thymosin beta-4 is another peptide with ocular surface activity, primarily in corneal wound healing and anti-inflammatory signaling. Zhai et al. (2022) showed that recombinant human thymosin beta-4 modulated anti-inflammatory responses in dry eye disease models.[9] For more on this peptide's corneal applications, see Thymosin Beta-4 for Corneal Healing: Eye Injury Research.
Substance P and neurokinin-1 receptor signaling also play roles in ocular surface homeostasis. Taketani et al. (2020) demonstrated that antagonizing substance P/neurokinin-1 receptor interactions restored regulatory T cell function in dry eye disease.[10] Zhang et al. (2025) found that tear neuropeptide levels correlate with both clinical symptoms and signs in dry eye patients, suggesting these peptides serve as biomarkers of disease severity.[11]
The distinctiveness of lacritin within this landscape is its mechanism: it is the only identified tear protein that directly stimulates tear production from the lacrimal gland rather than acting on inflammation, immunity, or wound healing. For the broader role of antimicrobial peptides in protecting the eye from infection, see Antimicrobial Peptides and Corneal Infections: Protecting Your Eyes.
The interplay between these peptide systems is relevant to understanding dry eye as a disease. When lacritin is depleted and tear production declines, the reduced tear volume concentrates inflammatory mediators on the ocular surface, activates nociceptive neuropeptide signaling (substance P, CGRP), and weakens the antimicrobial peptide barrier, increasing infection risk. Eshac et al. (2021) described this cycle in their review of endogenous antimicrobial peptides at the ocular surface, noting that tear deficiency creates a vicious circle: less fluid means more inflammation means more surface damage means further impairment of lacrimal and meibomian gland function.[8] Lacritin, by restoring the tear volume component of this cycle, could theoretically break the feedback loop at its origin rather than at a downstream point.
Nguyen et al. (2025) developed an engineered tandem thymosin peptide for corneal wound healing, demonstrating the growing interest in peptide-based ocular therapeutics.[12] The convergence of multiple peptide candidates (lacritin for tear secretion, thymosin beta-4 for wound healing, engineered antimicrobial peptides for infection) suggests that the next generation of dry eye treatment may involve peptide combinations targeting multiple aspects of ocular surface dysfunction simultaneously.
What the evidence does and does not show
The evidence for lacritin follows a clear trajectory from molecular discovery to clinical translation, with each step supported by published data. The protein was discovered and characterized (Sanghi 2001, Ma 2008), its receptor mechanism was defined (Dias-Teixeira 2020), its deficiency in dry eye was documented (Karnati 2013, Vijmasi 2014), its therapeutic potential was demonstrated in animal models (Vijmasi 2014), and its active fragment was tested in humans (Tauber 2023). This 22-year arc from gene cloning to first-in-human trial is typical of peptide drug development, where the biology must be thoroughly characterized before a viable therapeutic form can be identified.
The evidence base, while consistent, is thin by pharmaceutical standards. There is essentially one research group (Gordon Laurie's laboratory, first at UVA and later at Johns Hopkins) that has driven the field. Most of the key publications share overlapping authorship. This is not unusual for a novel target in early development, but it means that independent replication of key findings (particularly the prosecretory activity and the syndecan-1 binding mechanism) would strengthen the evidence considerably.
The limitations are equally clear. There is only one published human trial, and it was a Phase I/II study designed primarily for safety and tolerability. The efficacy endpoints were secondary. The trial was conducted exclusively in Sjogren's syndrome, which affects approximately 1-4 million Americans but represents a minority of the estimated 16 million Americans with dry eye disease. Whether Lacripep works in non-Sjogren's dry eye is an open question.
The 19-amino-acid Lacripep fragment retains the prosecretory activity of full-length lacritin, but it does not replicate all of the parent protein's functions. Full-length lacritin has N-terminal regions involved in cell targeting and potential additional signaling; whether the fragment captures enough of the biological activity for clinical efficacy at scale remains to be determined in larger trials.
There is also a manufacturing and stability question inherent to peptide therapeutics. Peptides in aqueous solution are susceptible to proteolytic degradation and aggregation. The three-times-daily dosing regimen in the Tauber trial suggests that Lacripep has a short duration of action on the ocular surface, which may limit patient compliance in a chronic disease requiring long-term treatment.
Despite these limitations, lacritin represents a genuinely novel approach to dry eye. It addresses the secretory deficit itself rather than inflammation or symptom management, and the human trial data, while preliminary, showed both statistical significance and a clinically meaningful speed of onset.
The question of whether lacritin can treat the broader dry eye population beyond Sjogren's is important because the majority of dry eye patients have evaporative dry eye (meibomian gland dysfunction) rather than aqueous-deficient dry eye. Lacritin's mechanism of action, stimulating aqueous tear secretion, is most directly relevant to aqueous deficiency. However, the autophagy and cell survival pathways could theoretically benefit ocular surface health regardless of the primary dry eye subtype. Clinical data in non-Sjogren's populations will be needed to resolve this question.
There is also a broader scientific question about why the lacrimal gland expresses lacritin so abundantly and why the tear film is uniquely dependent on this single protein for secretory homeostasis. No other exocrine gland in the body has an identified equivalent of lacritin, a dedicated prosecretory factor whose absence specifically impairs glandular function. Whether this reflects a unique vulnerability of the lacrimal gland or whether analogous proteins await discovery in other glands remains an open area of investigation.
The Bottom Line
Lacritin is the only known prosecretory tear protein, discovered in 2001 and systematically characterized over two decades. Its deficiency in multiple forms of dry eye disease, combined with restoration of tear production when replaced, supports a replacement therapy model analogous to insulin in diabetes. The first-in-human trial of its active fragment Lacripep showed significant improvements in both corneal staining and symptoms within two weeks in Sjogren's patients, with favorable safety. The evidence is promising but early: one Phase I/II trial in a specific patient population, with larger and longer studies needed to establish efficacy across the dry eye spectrum.