Single-Cell Sequencing Reveals Androgen Deficiency Arrests Meibocyte Differentiation and Impairs EMC-Mediated Lipid Metabolism
- 1State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- 2Ningbo Key Laboratory of Medical Research on Blinding Eye Diseases, Ningbo Eye Institute, Ningbo Eye Hospital, Wenzhou Medical University, Ningbo, China
Abstract
Purpose: To investigate the cellular dynamics of androgen-deficient meibomian gland dysfunction (MGD) and to elucidate the molecular mechanisms limiting the structural regenerative efficacy of topical dihydrotestosterone (DHT) treatment.
Methods: Single-cell RNA sequencing (scRNA-seq) was performed on meibomian glands from sham-operated controls, castrated mice, and castrated mice receiving topical 0.08% DHT. We performed comparative analyses to quantify changes in cell composition, reconstruct differentiation trajectories, and systematically profile alterations in metabolic pathways and organelle homeostasis networks.
Results: Castration arrested meibocyte differentiation and redirected cell fate commitment. Pseudotime trajectory analysis revealed a pronounced shift from the meibocyte lineage toward ductal and progenitor fates, accompanied by comprehensive downregulation of lipogenic genes (e.g., Fasn, Awat2). This fate reprogramming was coupled with disrupted endoplasmic reticulum (ER) homeostasis, including suppression of the ER membrane protein complex (EMC) and impaired lipid assembly machinery. Topical DHT treatment partially restored meibocyte differentiation but failed to fully recover gland morphology. Furthermore, rapid metabolic reactivation following DHT treatment outpaced ER capacity recovery, inducing proteostatic stress.
Conclusions: Androgen deficiency drives MGD through dual mechanisms: reprogramming of meibocyte cell fate toward non-lipogenic lineages and suppression of EMC-mediated stabilization of ER-resident lipogenic enzymes. The resulting temporal mismatch between lipogenic reactivation and ER capacity recovery upon DHT treatment induces proteostatic stress, limiting the efficacy of androgen monotherapy and identifying the EMC–ER axis as a candidate therapeutic target for combinatorial intervention.
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BibTeX
@article{qian2026singlecell,
title = {{Single-Cell Sequencing Reveals Androgen Deficiency Arrests Meibocyte Differentiation and Impairs EMC-Mediated Lipid Metabolism}},
author = {Shenchuan Qian and Zihao Liu and Mike Pan and Meiling Zhu and Juan Li and Yuyang Fu and Qian Li and Zhiwei Zha and Ying Feng and Wei Chen},
journal = {Investigative Ophthalmology \& Visual Science},
year = {2026},
month = oct,
doi = {10.1167/iovs.67.12.46},
url = {https://doi.org/10.1167/iovs.67.12.46},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Single-Cell Sequencing Reveals Androgen Deficiency Arrests Meibocyte Differentiation and Impairs EMC-Mediated Lipid Metabolism
AU - Shenchuan Qian
AU - Zihao Liu
AU - Mike Pan
AU - Meiling Zhu
AU - Juan Li
AU - Yuyang Fu
AU - Qian Li
AU - Zhiwei Zha
AU - Ying Feng
AU - Wei Chen
PY - 2026
DA - 2026/10/22
JO - Investigative Ophthalmology & Visual Science
DO - 10.1167/iovs.67.12.46
UR - https://doi.org/10.1167/iovs.67.12.46
AB - Purpose: To investigate the cellular dynamics of androgen-deficient meibomian gland dysfunction (MGD) and to elucidate the molecular mechanisms limiting the structural regenerative efficacy of topical dihydrotestosterone (DHT) treatment. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on meibomian glands from sham-operated controls, castrated mice, and castrated mice receiving topical 0.08% DHT. We performed comparative analyses to quantify changes in cell composition, reconstruct differentiation trajectories, and systematically profile alterations in metabolic pathways and organelle homeostasis networks. Results: Castration arrested meibocyte differentiation and redirected cell fate commitment. Pseudotime trajectory analysis revealed a pronounced shift from the meibocyte lineage toward ductal and progenitor fates, accompanied by comprehensive downregulation of lipogenic genes (e.g., Fasn, Awat2). This fate reprogramming was coupled with disrupted endoplasmic reticulum (ER) homeostasis, including suppression of the ER membrane protein complex (EMC) and impaired lipid assembly machinery. Topical DHT treatment partially restored meibocyte differentiation but failed to fully recover gland morphology. Furthermore, rapid metabolic reactivation following DHT treatment outpaced ER capacity recovery, inducing proteostatic stress. Conclusions: Androgen deficiency drives MGD through dual mechanisms: reprogramming of meibocyte cell fate toward non-lipogenic lineages and suppression of EMC-mediated stabilization of ER-resident lipogenic enzymes. The resulting temporal mismatch between lipogenic reactivation and ER capacity recovery upon DHT treatment induces proteostatic stress, limiting the efficacy of androgen monotherapy and identifying the EMC–ER axis as a candidate therapeutic target for combinatorial intervention.
SN - 0146-0404
SN - 1552-5783
ER -