BHMT Protects Against Diabetic Cataracts by Reducing Homocysteine and Counteracting Endoplasmic Reticulum Stress in Lens Epithelial Cells.

Betaine homocysteine S-methyltransferase (BHMT) is crucial in the regulation of various metabolic disorders by managing the elimination of homocysteine (Hcy). However, the function of the BHMT-Hcy regulatory axis in diabetic cataract is not yet fully understood. The objective of this research was to explore the regulatory effects of the BHMT-Hcy axis on diabetic cataracts and its potential molecular mechanisms via in vivo and in vitro models. Diabetic cataract models were established in vivo via streptozotocin-induced diabetic rats and in vitro via lens epithelial cells exposed to high glucose (HG). Western blotting demonstrated reduced BHMT levels in both models, alongside a concomitant elevation in Hcy concentrations. Lens epithelial cells were transduced with recombinant adenovirus to induce either BHMT overexpression or silencing. A series of biological assays, including CCK-8, TUNEL, and oxidative stress assays, were subsequently conducted to evaluate the effects of BHMT on HG–induced cellular injury. BHMT overexpression in lens epithelial cells exposed to HG increased viability from 46.7 ± 4.2% to 84.6 ± 6.4% and decreased the percentage of apoptotic cells from 34.3 ± 4.8% to 11.2 ± 3.5%. Measurements of oxidative stress revealed that BHMT overexpression lowered ROS and MDA levels while increasing SOD levels. Western blotting analysis demonstrated that BHMT overexpression inhibited both epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum stress (ERS) induced by HG in lens epithelial cells. Notably, these protective effects of BHMT were reversed by the addition of Hcy. Additionally, BHMT silencing exacerbated HG-induced cellular injury, which could be alleviated through treatment with ERS inhibitors. In vivo, BHMT overexpression was achieved in rats via intravitreal injection of adeno-associated virus. Slit-lamp examination revealed that BHMT overexpression significantly decreased the cataract grade score from 3.2 ± 0.5 to 2.2 ± 0.3 in diabetic cataract model rats. Consistently, western blotting and biological assays in lens tissue demonstrated that BHMT overexpression suppressed ERS and oxidative stress in the diabetic cataract model. Collectively, our findings suggest that BHMT reduces Hcy levels, thereby inhibiting ERS and subsequent HG-induced cellular injury, ultimately delaying cataract progression. This research not only provides new insights into the pathogenesis of diabetic cataracts but also identifies BHMT as a promising therapeutic target for its prevention and management.