Abstract

Purpose:Meibomian gland (MG) atrophy in Meibomian gland dysfunction (MGD) is critically linked to progenitor cell (PC) abnormalities. However, the mechanisms underlying PC abnormalities during MGD pathogenesis remain unclear. This study investigates the role of ferroptosis in MG PC abnormalities during MGD pathogenesis.Methods:Three mouse MGD models were established: alkali burn-induced MGD (AK-MGD), blue light-induced MGD (BL-MGD), and age-related MGD (AR-MGD). All exhibited MG atrophy and Lrig1-positive PC abnormalities. Dihydroethidium (DHE) and immunofluorescent staining for Gpx4 and Ptgs2 in MGs were applied to observe the distribution of ferroptotic cells during MGD. Ferroptosis was evaluated in H2O2-treated human MG epithelial cells (HMGECs) by measuring intracellular Fe2+, iron metabolism gene expression, and levels of Gpx4, Slc7a11, and Ptgs2. Ferroptosis signatures were evaluated across models. Ferroptosis inhibitors including Ferrostatin-1 (Fer-1), deferoxamine (DFO), and N-acetylcysteine (NAC) targeting different ferroptosis pathways were applied therapeutically in these MGD models.Results:All MGD models demonstrated lipid peroxidation and ferroptosis in MG PCs. In HMGECs, we confirmed that H2O2treatment induced ferroptosis, which was rescued by ferroptosis inhibitors. Acute and chronic MGD models exhibited distinct ferroptosis signatures. Therapeutic intervention with ferroptosis inhibitors ameliorated MGD manifestations to varying degrees in MGD models.Conclusions:Ferroptosis in MG PCs contributes to the pathogenesis of MGD. MG PCs are preferentially susceptible to ferroptosis. Pharmacological inhibition of ferroptosis represents a promising therapeutic strategy for MGD.