As a group of endocrine and metabolic diseases characterized by hyperglycemia (Gothai et al., 2016), diabetes mellitus (DM) exhibits increasing incidence and mortality rates lately, particularly in developed countries (Shaw et al., 2010). Diabetic cataract (DC), featured with opacification in eye lens, is an early and major ocular complication of DM (Madsen-Bouterse et al., 2008) and may lead to vision loss and even blindness in the worst case (Pollreisz et al., 2010). Although cataract surgery is the only cure for DC so far (Simunovic et al., 2018), it carries a high risk of postoperative complications (Furino et al., 2021). Hence, an in-depth understanding of DC and the development of effective therapeutic agents are still top priorities for current research on DC.

DC pathogenesis is a multifactorial process that hasn't been well understood (Floud et al., 2016). Emerging evidence suggests that oxidative stress and epithelial-mesenchymal transition (EMT) are the foremost causes of cataract formation (Spector, 1995; Chen et al., 2017a). Prior studies also revealed hyperglycemia may induce apoptosis (Yao et al., 2020), EMT (Li et al., 2022), and oxidative stress damage (Kyselova et al., 2004), thus promoting DC development. Lens epithelial cells (LECs) are responsible for lens function (He et al., 2019). Previous reports have shown that high glucose (HG)-triggered apoptosis, EMT and oxidative stress in LECs contribute to DC initiation and progression (Fu et al., 2022). Therefore, reducing LEC apoptosis, EMT, and oxidative stress can be a strategy to treat DC.

Dichloroacetate (DCA), a potent pyruvate dehydrogenase kinase inhibitor, promotes utilization of carbohydrates by accelerating the conversion of pyruvate to acetyl-coA, thereby boosting metabolic flexibility (Hansen et al., 2022). Therefore, DCA could improve metabolic dysfunction in certain disorders, such as sepsis-induced hepatic metabolic dysfunction (Mainali et al., 2021), lactic acidosis (Bennett et al., 2020), and hypercholesterolemia (Moore et al., 1979). Besides, DCA reduces DM-induced hyperglycemia by stimulating peripheral glucose utilization and inhibiting gluconeogenesis (Weber, 2016). In addition, DCA also improves DM complications, including diabetic cardiomyopathy (Hansen et al., 2022) and diabetic ketoacidosis (Backshear et al., 1975). Of note, DCA could mitigate retinal degeneration in rd10 mice (Kanan et al., 2022) and inhibits EMT in the cellular model of proliferative retinopathies (Shukal et al., 2020), implying its protective role against ophthalmic disorders. Nevertheless, the role of DCA in DC has not been investigated yet.

In this work, we aimed to determine the effect of DCA in DC and investigate the underlying molecular mechanism in vivo and in vitro by using a murine model of streptozotocin (STZ)-induced Sprague-Dawley (SD) rats and a cellular model of HG-treated SRA-01/04 cells.