COL1A1 regulates the progression of dry eye disease through metabolic reprogramming and inflammatory responses via the HIF1A/HK2 pathway.

Dry eye disease (DED) is a prevalent ocular surface disorder with complex pathogenesis involving glycolytic reprogramming and inflammation. This study aims to investigate whether collagen type I alpha 1 chain (COL1A1) modulates metabolic dysregulation and inflammatory responses in DED, and to evaluate its potential as a disease-modifying therapeutic target through the hypoxia-inducible factor-1α (HIF1A)/hexokinase 2 (HK2) pathway. In vitro, human corneal epithelial cells (HCEs) were exposed to hyperosmotic stress; COL1A1 overexpression and COL1A1-HIF1A co-overexpression were performed. In vivo, a DED mouse model was induced via scopolamine injection and low humidity, with adeno-associated virus (AAV)-mediated Col1a1/Hif1a overexpression. Assessments included qRT-PCR, Western blotting, ELISA, lactate assay, extracellular acidification rate (ECAR) measurement, transepithelial electrical resistance (TEER), tear secretion test, and Periodic Acid-Schiff (PAS) staining. In a scopolamine-induced DED mouse model, Col1a1 overexpression significantly restored tear secretion and increased conjunctival goblet cell density, both of which were markedly impaired under disease conditions. At the cellular level, COL1A1 expression was downregulated under hyperosmotic stress, whereas HIF1A/HK2 signaling and glycolytic activity were upregulated. COL1A1 overexpression suppressed HIF1A/HK2 activation, reduced glycolysis, decreased interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels, and improved epithelial viability and tight junction integrity. These protective effects were abolished by HIF1A co-overexpression, confirming that COL1A1 alleviates metabolic and inflammatory dysfunction primarily through inhibition of the HIF1A/HK2 signaling axis. COL1A1 alleviates DED by suppressing HIF1A/HK2-mediated glycolytic reprogramming and inflammation, thereby improving ocular surface function. These findings identify COL1A1 as a novel metabolic regulator and highlight its potential as a disease-modifying therapeutic target for dry eye disease.