The Underlying Mechanisms of Progressive Meibomian Gland Dysfunction

Key Takeaways:

• Progressive MGD is primarily driven by ductal hyperkeratinization, which causes obstruction, meibum stasis, and irreversible acinar atrophy.
• Emerging research identifies age-related cellular failures, including stem cell senescence and metabolic (NAD+) decline, as key underlying pathogenic mechanisms.
• Preclinical studies will test whether activating Hh and EGFR signaling with small molecules can rescue age-related meibomian gland degeneration.

Meibomian gland dysfunction (MGD) is a primary driver of dry eye disease, a condition encountered daily in clinical practice. It is defined by qualitative or quantitative deficiencies in meibum, the lipid secretion essential for tear film stability. This dysfunction is notably progressive. Without intervention, it often leads to chronic patient discomfort and ocular surface damage.¹

The meibomian glands are large sebaceous glands whose lipids form the superficial layer of the tear film, which helps slow evaporation. In MGD, this function fails due to gland obstruction and, ultimately, atrophy.¹

Underlying mechanisms of progressive MGD

Emerging research is actively elucidating the complex cellular and molecular pathways that underpin MGD progression. Understanding these mechanisms is critical for moving beyond palliative treatments toward disease-modifying interventions.^1-5

Obstructive MGD and gland atrophy

The most prevalent form is obstructive MGD, characterized by terminal duct obstruction. The primary pathogenic mechanism is hyperkeratinization of the ductal epithelium. This process leads to the formation of a plug of sloughed epithelial cells and viscous meibum.¹

This obstruction increases intraductal pressure. The resulting stasis causes acinar dilation and subsequent progressive atrophy of the secretory acini. This pressure can also damage the supporting gland architecture. The resulting gland dropout is non-reversible. This loss of functional secretory tissue directly correlates with the severity of meibum deficiency and clinical symptoms.^1,2

Age-related cellular mechanisms

Aging is a principal risk factor for MGD. Recent research has identified specific cellular failures that drive this age-related decline.¹

Stem cell deterioration

Meibomian gland homeostasis and repair rely on resident stem cell populations. A 2025 study identified that the Hedgehog (Hh) signaling pathway is crucial for maintaining this stem cell activity. Research indicates that with aging, Hh signaling attenuates. This attenuation leads to reduced stem cell proliferation and regenerative capacity. This failure in tissue maintenance and repair is a key mechanism driving age-related gland dysfunction and loss.³

Metabolic decline

Meibum synthesis is an energy-intensive biochemical process. A 2022 study highlighted the role of nicotinamide adenine dinucleotide (NAD+), a key coenzyme in cellular metabolism. NAD+ levels were found to decline with age in meibomian gland tissue. This metabolic deficit impairs the acinar cells' ability to synthesize lipids effectively. This finding suggests that age-related MGD is, in part, a disease of cellular energy failure.^1,4

Transcriptional regulation

Specific transcription factors are essential for gland development and function. A 2021 study identified the Krox20 protein as a critical regulator for meibomian gland morphogenesis and homeostasis.⁵

The absence or dysfunction of Krox20 disrupts normal acinar development and maintenance. This disruption leads to gland abnormalities and severe dry eye phenotypes, identifying Krox20 as a key player in gland integrity.⁵

Contributing comorbidities and factors

While aging is intrinsic, extrinsic factors and comorbidities often accelerate MGD, such as:^1,2

• Inflammation – Chronic blepharitis and inflammatory skin conditions, such as rosacea, are strongly associated with MGD. Pro-inflammatory mediators can alter meibum composition and contribute directly to ductal hyperkeratinization.
• Hormonal regulation – Androgens are known to positively regulate meibomian gland function and lipid synthesis. Therefore, hormonal fluctuations or deficiencies can disrupt meibum production and quality, contributing to dysfunction.
• Microbial factors – Alterations in the eyelid microbiome, including bacterial overgrowth (e.g., Staphylococcus species) or Demodex mites, are implicated in MGD. These organisms can trigger localized inflammation, physically obstruct gland orifices, and degrade the meibum, further destabilizing the tear film.
  

  Autoimmune-mediated MGD

  In patients with systemic autoimmune conditions, particularly Sjögren’s Disease, the pathophysiology of MGD is distinct. The mechanism is not primarily obstructive but rather destructive. It involves lymphocytic infiltration of the exocrine glands.⁶

  This autoimmune-driven inflammation, often T-cell mediated, causes acinar cell death, fibrosis, and progressive, irreversible gland atrophy. This form of MGD is often more severe and less responsive to traditional obstructive MGD treatments.⁶

  Clinical and research implications

  This evolving understanding of MGD pathophysiology is shifting the treatment paradigm beyond simple mechanical expression or warm compresses. Future therapeutic strategies may target these underlying mechanisms directly.¹

  Treating MGD often starts with care you can do at home. This includes daily warm compresses and lid hygiene to help clear away buildup. However, these at-home treatments are only partially effective.³

  Current research, involving preclinical studies, is working to determine whether small molecules that activate Hh and EGFR signaling can effectively rescue age-related meibomian gland degeneration. The hope is that this work will eventually result in new, more effective therapies for people living with MGD.³

  For clinicians, recognizing the multifactorial nature of MGD is essential for tailoring treatment. Identifying the predominant pathogenic driver in a given patient – whether obstructive, atrophic, inflammatory, or autoimmune – will be key to optimizing patient outcomes.^1,3