PANK4 Regulates YAP to Modulate the Glycolytic Pathway in LEC for Driving LECs-EMT in Early Diabetic Cataract...

Lens epithelial cell-mesenchymal transition (LEC-EMT) is the key process in diabetic cataract (DC). Although PANK4 is known to suppress LEC-EMT, its mechanism remains unclear. This study aims to elucidate the role of PANK4 in DC pathogenesis through the YAP/TAZ pathway.

We established diabetic mice and high-glucose-stimulated LECs. Interventions included PANK4 overexpression/knockdown and YAP inhibitor treatment. Protein expression was analyzed by Western blotting and immunofluorescence. Anterior capsule damage was assessed via slit-lamp after anterior chamber injection of si-PANK4 or YAP inhibitor in diabetic mice. LECs' functional assays included EdU, phalloidin staining, and scratch-wound assays.

PANK4 and EMT markers were significantly upregulated in diabetic mice, and PANK4-overexpression upregulated EMT markers and YAP in LECs. Immunoprecipitation confirmed PANK4-YAP physical interaction in the lens. PANK4-knockdown of LECs and high-glucose-stimulated lens suppressed the expression of α-SMA and YAP, enhanced LECs' proliferation, and reduced the migration. Most importantly, si-PANK4 or YAP inhibition alleviated induced anterior capsule damage in diabetic mice. The si-PANK4 significantly downregulated EMT markers and YAP, and reversed the phosphorylation state of YAP in the lens. YAP inhibitor treatment in PANK4-overexpressing LECs similarly downregulated EMT/YAP markers and replicated the functional effects of si-PANK4 in the lens. High glucose and PANK4-overexpression upregulated HK2, LDHA, and YAP/TAZ expression, and both PANK4-knockdown and YAP inhibition reversed these effects.

Under hyperglycemia, PANK4 activates the YAP/TAZ pathway to upregulate glycolytic enzymes (HK2/LDHA), driving LEC-EMT and early DC progression. In vivo inhibition of PANK4 or YAP alleviates anterior capsule damage, highlighting the PANK4-YAP-glycolysis-EMT axis as a promising therapeutic target for DC.