Ocular social jetlag: a driver of immune-metabolic dysfunction in dry eye disease

SJL perturbs light–sleep–feeding cycles, thereby disturbing local clocks in the lacrimal gland, meibomian gland, cornea, and conjunctiva. Because these tissues differ markedly in function, the initial manifestations of clock disruption are tissue specific.

In the lacrimal gland, which depends strongly on circadian regulation for secretory activity, chronic phase-advance models reveal widespread remodeling of the circadian transcriptome, with more than 2,000 rhythmic transcripts showing phase shifts or loss of oscillation, including genes involved in metabolic and immune pathways. This disturbance is accompanied by attenuation of diurnal variation in gland weight, acinar cell size, and pilocarpine-stimulated tear secretion (44). Prolonged circadian disruption or sleep deprivation further leads to excessive accumulation of ROS, upregulation of the DNA damage marker γ-H2AX, and structural abnormalities of acini, culminating in irreversible tear hyposecretion (45). Mechanistic evidence is provided by postoperative dry eye models, in which surgical stress selectively downregulates Nr1d2 (REV-ERBβ) in the lacrimal gland, impairing mitochondrial function and lipid metabolism; pharmacological activation of REV-ERB reverses these metabolic defects and restores tear secretion (11, 46). Corneal nerve injury models further demonstrate that peripheral neural input is required to maintain lacrimal clock integrity, whereas metabolic disease models (db/db mice) show that systemic metabolic dysfunction alone can abolish approximately half of rhythmic lacrimal genes and advance the phase of the remaining oscillations (62, 63).

Corneal and conjunctival homeostasis relies on precise temporal gating. In the cornea, BMAL1 directly regulates transcription of the transmembrane mucin MUC4, and both chronic circadian misalignment and Bmal1 deficiency markedly reduce MUC4 expression, compromising tear film stability and epithelial barrier integrity; supplementation of MUC4 or restoration of BMAL1 activity by melatonin improves barrier function. Hypoxic stress selectively reshapes corneal clock gene rhythms, with peak disruption coinciding with epithelial defects, reduced nerve density, and neutrophil infiltration (57). In the conjunctiva, SJL downregulates the BMAL1–REV-ERBα axis, thereby derepressing IL-17 transcription and promoting Th17-associated inflammation; melatonin restores this axis and suppresses IL-17 expression (47). Hypomethylation of PER2 and PER3 promoters in experimental dry eye models further indicates that inflammatory environments can epigenetically modify clock components (61).

Notably, clock disruption is not merely upstream of inflammation but engages in bidirectional interactions. IL-17 and the NF-κB pathway can directly inhibit BMAL1/CLOCK transcriptional activity, establishing a feedforward loop in which circadian misalignment promotes low-grade inflammation and metabolic stress, which in turn further suppress circadian regulation (56, 61).

Across models, oxidative stress emerges as a central hub linking circadian misalignment to inflammatory responses. Both mitochondrial dysfunction in the lacrimal gland and environmental stress in corneal and conjunctival epithelia (57) converge on ROS accumulation, which functions as both a marker of metabolic imbalance and a potent inflammatory trigger.

In lacrimal gland models combining sleep deprivation and silica nanoparticle exposure, a complete ROS–NLRP3–JAK2/STAT3–NF-κB–IL-17A signaling axis has been directly validated. Circadian disruption and particulate stress synergistically induce ROS accumulation, trigger NLRP3 inflammasome assembly, and activate JAK2/STAT3 and NF-κB p65 phosphorylation, resulting in marked upregulation of IL-17A. Activation of this axis is directly associated with lacrimal gland atrophy and reduced secretion (48). Although NLRP3 activation can promote gasdermin D–dependent pyroptosis, direct evidence for specific cell death modalities in SJL-related ocular models remains limited and should be interpreted cautiously (64).

Other inflammatory pathways may also participate. The TLR4/MyD88/NF-κB axis is activated in diabetic dry eye, and its inhibition attenuates corneal inflammation (49). In nonalcoholic steatohepatitis models, melatonin suppresses both TLR4/NF-κB signaling and NLRP3 activation (50), suggesting that circadian regulators integrate with innate immune pathways under metabolic stress. The cGAS–STING pathway, which senses cytosolic mitochondrial DNA, has been implicated in dry eye–associated inflammation (51, 52), and sleep deprivation–induced mtDNA release has been shown to activate cGAS–STING signaling in prostatitis models (53), providing a mechanistic analogue linking circadian disruption to innate immune activation.

Ferroptosis represents another potential, yet unverified link. Corneal tissues from dry eye models display lipid peroxidation, glutathione depletion, mitochondrial structural abnormalities, and differential expression of ferroptosis-related genes including ARNTL (Bmal1). In traumatic brain injury, BMAL1 downregulation enhances neuronal susceptibility to ferroptosis, whereas ferroptosis inhibition partially restores clock gene expression (55). Although direct evidence connecting SJL to ocular ferroptosis is lacking, these findings support a plausible hypothesis that clock disruption may increase epithelial vulnerability to ferroptotic stress.

Sustained metabolic and inflammatory stress ultimately disrupts the three principal systems maintaining ocular surface integrity. In the lacrimal gland, combined clock dysregulation, oxidative injury, and inflammatory signaling produce acinar vacuolization and atrophy, with irreversible declines in basal and reflex tear secretion, accompanied by structural degeneration (39, 45, 46). At the molecular level, BMAL1 directly regulates transcription of ITPR2/3, linking clock disruption to impaired secretory capacity (56). In the meibomian gland, loss of rhythmic NAD⁺ synthesis suppresses the activity of the NAD⁺-dependent enzyme 3β-hydroxysteroid dehydrogenase, reducing local androgen production and promoting acinar atrophy, ductal hyperkeratinization, and altered lipid composition (58–60). Concurrent loss of corneal MUC4 expression weakens tear film anchoring (39). IL-17-driven disruption of epithelial tight junctions, together with an unstable lipid layer, accelerates evaporation, resulting in hyperosmolar stress and sensory nerve exposure (65).

These pathological changes extend beyond local tissue damage. Photophobia and chronic ocular discomfort lead to reduced daytime outdoor activity, increased nighttime screen exposure, and delayed sleep onset (66). Progressive deterioration in sleep quality further impairs central–peripheral circadian synchronization, reinforcing the underlying clock misalignment (67). Through this process, an initially reversible circadian disturbance becomes embedded within a self-sustaining cycle linking environmental stress, multitissue dysfunction, clinical symptoms, and maladaptive behaviors. The concept of “ocular social jetlag” introduced herein advocates for a fundamental paradigm shift in understanding DED. To crystallize the core dimensions of this shift, the traditional view is systematically contrasted with the emerging framework in Table 2.

Traditional diagnostics rely on subjective recall and single-time-point assessments, often missing dynamic disease progression. Key pathological events, such as diurnal reductions in meibomian gland lipid secretion and nocturnal accumulation of tear inflammatory mediators, vary continuously over time. Emerging technologies offer potential to capture rhythm parameters, including phase, amplitude, and waveform, but most remain experimental with limited validation in clinical dry eye populations.

For example, computer vision-based blink analysis focuses on the rhythmic entropy of blink intervals, a measure of interval regularity. Healthy individuals display longer but regular intervals (low entropy) during daytime visual tasks, whereas early dry eye patients show increasing irregularity (high entropy) with prolonged task duration, reflecting impaired rhythmic buffering in neural feedback loops for surface hydration and consequent decompensation (68, 69). These preliminary findings provide a foundation for dynamic monitoring but require larger clinical studies for confirmation. Wearable tear sensors, such as fluorescent hydrogel patches, aim to map 24-hour profiles of immune molecules like lysozyme and MMP-9. A recent fluorescent MOF hydrogel patch achieved high-sensitivity lysozyme detection (limit 1.5 nM) analyzable via smartphone apps (70), though long-term validation in dry eye patients is pending. Multichannel nanophotonic immunosensors, nanowire field-effect transistors, and antibody microarrays enable ultrasensitive, real-time multiplex detection (e.g., MMP-9, lysozyme, lactoferrin) with minimal sample requirements and ease of use (71–73). Despite these promising proofs-of-concept, a significant gap remains between laboratory-scale engineering performance and robust clinical evidence. Current wearable tear sensors are primarily validated in small cohorts or healthy subjects over short durations, failing to capture the long-term heterogeneity of DED populations (71). Technologically, the translation from prototype to clinic faces several critical barriers. First, the limited tear volume and its high susceptibility to evaporation and environmental noise make precise quantification difficult; furthermore, the very presence of a sensor may trigger reflexive tearing, diluting biomarker concentrations and introducing sampling bias (70). Second, sensor-tissue interfaces are prone to bio-fouling, the non-specific adsorption of proteins and lipids, which leads to signal drift and reduced stability during 24-hour monitoring (74). Third, achieving reliable multiplexing without signal crosstalk remains an engineering challenge for simultaneous detection of cytokines like MMP-9 and lysozyme. Beyond technical hurdles, the path to clinical adoption requires scaling from nanofabrication to GMP-compliant mass production and navigating complex regulatory frameworks such as FDA or ISO certifications (75). Consequently, the direct linkage between these digital signals and specific immune phenotypes remains conceptual and awaits rigorous validation in multi-center clinical trials.

Circadian disruptions represent cross-system, multi-timescale desynchronization processes. Constructing a digital immune phenotype therefore emphasizes reconstructing synchronization across multimodal time series rather than isolated metrics. Due to current technological limitations, this relies on accessible neurophysiological, behavioral, and systemic rhythm signals, not direct continuous measurements of local ocular surface rhythms, making the signal-to-phenotype translation a conceptual framework.

Video-based facial and ocular analysis reliably extracts blink frequency, eyelid closure dynamics, and heart rate, aligning with contact sensors and distinguishing resting from task-loaded states (76, 77). These metrics reflect the dynamic regulatory state of the central-autonomic nervous system and serve as a feasible, remote, non-invasive entry point for rhythm monitoring, but they are not direct proxies for the tear film or ocular surface immune microenvironment.

In chronomedicine, wearable devices collect longitudinal activity-rest rhythms, heart rate variability, sleep, and light exposure data, quantified using parametric and nonparametric methods to assess phase, amplitude, and stability (78–80). These approaches are primarily derived from systemic chronomedicine and inflammatory disease studies, with limited direct ocular evidence; thus, they serve as referential analogies rather than confirmations. Integrating data across temporal resolutions and biological levels is critical to understanding circadian disruptions (79). Accordingly, ocular signals function as observable nodes in systemic rhythm networks, not independent local clocks. Coordinated changes in pupillary dynamics, oculomotor parameters, and heart rate variability reveal autonomic response patterns and stress adaptation subtypes, suggesting that circadian disruptions manifest as multimodal signal coupling reorganizations beyond single-metric anomalies (81).

In summary, current personalized circadian disruption networks integrate ocular neurobehavioral signals with systemic rhythm parameters over time. Analyses of synchrony and phase relationships aim to explore social jetlag-associated rhythm reprogramming. Digital mapping of tear film and ocular surface immune rhythms awaits advances in sensing technologies and physiological validation to strengthen the rationale for linking signal detection to immune phenotyping.

DED symptoms and ocular surface inflammatory markers exhibit diurnal variation (82, 83). Aligning anti-inflammatory treatment with these inflammatory windows may therefore enhance efficacy while reducing adverse effects. Drawing on established chronotherapeutic approaches in systemic immune inflammatory diseases such as rheumatoid arthritis (84), we propose the hypothesis that administration of intermediate or long-acting topical formulations, for example gels or liposomes, at bedtime, targeting nocturnal innate immune activation in DED, may more effectively suppress the morning inflammatory peak while reducing cumulative daytime exposure. Although direct evidence in DED is currently lacking, a recent study reporting the efficacy and safety of pulsed low dose hydrocortisone in Sjögren’s syndrome related DED (85), provides preliminary support for the feasibility of this approach.

At present, melatonin is the circadian-related molecule with the greatest translational potential. In addition to pineal secretion, melatonin is locally synthesized at the ocular surface and signals through MT1 and MT2 receptors, forming a relatively independent regulatory system (86). Multiple preclinical studies have demonstrated that melatonin attenuates inflammation, oxidative stress, and glandular dysfunction in DED models (Table 3). A pilot clinical study in primary Sjögren’s syndrome associated DED showed that oral melatonin at 5 mg per day for 8 weeks improved tear secretion, tear film stability, and symptom scores, while reducing serum IL-6 levels with good tolerability (93), providing human evidence for its systemic immunomodulatory potential. In parallel, delivery platforms such as nanoliposomes and drug eluting contact lenses are being explored to enhance ocular bioavailability and retention.

By contrast, direct targeting of core clock transcription factors such as REV-ERB and RORα remains at an early stage. Animal studies suggest that REV-ERB agonists can alleviate LPS-induced ocular inflammation (94), while inverse agonists of RORα or γt improve glandular function in Sjögren’s syndrome models (95). Moreover, downregulation of lacrimal gland Nr1d2 in postoperative DED mice leads to lipid metabolic disturbances, which can be partially reversed by the agonist SR9011 (46). These findings indicate that core clock pathways may represent upstream therapeutic targets in specific DED contexts, although their translational value requires systematic validation.

Management of the two strongest zeitgebers, light exposure and feeding time, aims to stabilize the overall biological clock and may indirectly attenuate systemic immune inflammation. Nocturnal artificial light suppresses melatonin secretion, disrupts clock gene expression, and is associated with low grade systemic inflammation (96). Therefore, for DED patients with social jetlag, increased daytime exposure to natural light and reduction of blue light exposure before bedtime are suggested (97–99). Although there is no direct clinical evidence in DED, such measures may create a more favorable internal environment for ocular surface repair by improving sleep and global immune balance.

In addition, time-restricted eating effectively synchronizes peripheral metabolic clocks and improves metabolic inflammation (100). In DED patients with metabolic risk factors such as MGD, time restricted eating may indirectly support meibomian gland function by optimizing systemic lipid metabolism and inflammatory status (101). At present, these interventions remain hypothesis generating strategies due to the lack of direct clinical evidence in DED.

Future management paradigms may integrate digital health technologies. Continuous passive collection of behavioral data including sleep, activity, and light exposure via wearables and smartphones, combined with patient reported outcomes and even home based ocular surface monitoring, could enable construction of individualized circadian health profiles (102). On this basis, artificial intelligence algorithms may identify patterns of circadian misalignment and deliver real time, context specific micro interventions, for example stand up and seek natural light or reduce screen exposure 30 minutes earlier tonight, forming a quantifiable, feedback driven monitor intervene optimize loop (103). This approach may overcome the limitations of conventional lifestyle advice and provide a sustainable strategy for chronic DED management.

It must be acknowledged that the circadian centered framework presented here is primarily supported by evidence derived from relatively young patient populations characterized by lifestyle related immunometabolic dysregulation, such as excessive digital screen use, sleep deprivation, and social jetlag. These patients typically present with prominent symptoms but relatively mild structural abnormalities, for example limited meibomian gland atrophy or lacrimal gland damage. In this circadian sensitive DED subtype, chronobiological interventions may be most effective.

However, DED is highly heterogeneous. In classical subtypes driven predominantly by overt structural damage, such as lacrimal gland fibrosis in advanced Sjögren’s syndrome or severe cicatricial meibomian gland dysfunction, circadian disruption is more likely to act as a concomitant or aggravating factor rather than a primary driver. In these settings, circadian interventions should be positioned as adjunctive and supportive strategies aimed at optimizing overall health, improving sleep quality, and potentially enhancing responsiveness to baseline therapies, such as immunosuppressants or physical treatments, rather than replacing conventional approaches.

Looking ahead, several key evidence gaps must be addressed. First, longitudinal studies across different DED etiologies and severities are needed to validate core clock gene expression patterns and to delineate regulatory networks within specific ocular surface immune cell populations. Second, rigorously designed randomized controlled trials targeting melatonin and other clock modulating molecules are required to establish efficacy and safety. Finally, the development and validation of user friendly, clinically applicable tools for circadian assessment and management are essential for translating this emerging concept into routine practice. Only through such stepwise investigation can chronobiology make a substantive contribution to precision and personalized therapy in DED.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.