Molecular mechanisms and pathophysiology of meibomian gland dysfunction

Meibomian gland dysfunction (MGD) is the leading cause of evaporative dry eye disease and arises from failure of a coordinated molecular network that normally maintains meibomian gland homeostasis. In health, endocrine-lipidogenic signaling via peroxisome proliferator-activated receptor-γ (PPARγ) and androgen receptor (AR), trophic pathways such as epidermal growth factor and Hedgehog, a circadian-metabolic axis coupling nicotinamide adenine dinucleotide (NAD⁺)-dependent steroidogenesis to lipid output, and neuroimmune circuits involving Toll-like receptors and nuclear factor-κB (NF-κB) act together to regulate stem/progenitor maintenance, meibocyte differentiation and lipid secretion. In MGD these axes become progressively uncoupled: hormonal and metabolic stress reduce NAD⁺ and intracrine androgen production, dampening AR-PPARγ activity; loss of trophic support exhausts basal progenitor pools; and chronic NF-κB-driven inflammation with Th17 and interleukin-33 (IL-33) signaling promotes ductal hyperkeratinization, acinar loss and fibrosis. Lipidomic studies show a shift from cholesteryl esters (CEs) toward free fatty acids, along with remodeling of O-acyl-ω-hydroxy fatty acid (OAHFA) profiles, oxidized lipids and eicosanoids, which stiffen meibum, destabilize the tear film lipid layer and fuel inflammation. Recent single-cell and organoid studies further map cellular heterogeneity and disease-linked lineage changes. Biomarkers such as cholesteryl ester/wax ester ratios, OAHFA profiles, eicosanoids, cytokines and imaging metrics offer read-outs of axis-specific dysfunction. Therapeutically, emerging strategies seek to correct these defects by enhancing AR-PPARγ signaling and NAD⁺-dependent steroidogenesis, re-engaging trophic pathways, normalizing ductal keratinization with "soft" keratolytics and inhibiting inflammatory circuits. This review integrates these mechanisms, disease networks, biomarker signatures and interventions into a unified model to support mechanism-based, biomarker guided precision care in MGD.