Aqueous humor levels of H3K18 lactylation and IL-1β reflect epigenetic-inflammatory activation in lens epithelium and serve as novel potential biomarkers for cataract diagnosis

Purpose: This study aimed to investigate the function and diagnostic potential of histone lactylation, specifically H3K18la, in cataract.

Methods: This study enrolled 72 participants, including 36 cataract patients and 36 control volunteers undergoing non-cataract intraocular surgery. Aqueous humor (AH) samples were collected from all subjects. The human lens epithelial cell line SRA01/04 was treated with transforming growth factor (TGF)-β2 to model cataractogenesis. Protein levels of global lactylation and H3K18la were assessed by Western blot. Metabolic activity was evaluated by measuring lactate production and glucose uptake, while oxidative stress was indicated by malondialdehyde levels. Inflammatory cytokine expression was quantified by real-time-quantitative polymerase chain reaction, and the direct binding of H3K18la to the IL-1β promoter was confirmed by chromatin immunoprecipitation-qPCR. The diagnostic value of biomarkers was analyzed using receiver operating characteristic curves.

Results: AH from cataract patients and TGF-β2-treated SRA01/04 cells exhibited elevated levels of global lactylation and H3K18la. ROC analysis demonstrated high potential diagnostic accuracy for both total lactylation and H3K18la in AH samples. Clinically, high H3K18la expression was significantly correlated with older age (≥65 years) and greater cataract severity. In vitro, lactic acid treatment enhanced H3K18la levels and amplified TGF-β2-induced metabolic shifts and oxidative stress. Mechanistically, H3K18la directly bound to the IL-1β promoter and activated its transcription. Finally, IL-1β mRNA was significantly upregulated in patient AH and also showed high potential diagnostic value.

Conclusions: H3K18la-driven transcriptional activation of IL-1β is associated with cataract development. H3K18la and IL-1β in the aqueous humor represent promising and sensitive potential biomarkers for the diagnosis of cataract.

Aqueous humor; Cataract; Diagnosis; H3K18la; Histone lactylation; IL-1β.