<p>Oxidative stress-induced endoplasmic reticulum stress (ERS) and mitochondrial dysfunction have been implicated as major contributors to lens epithelial cell (LEC) apoptosis in age-related cataract (ARC); however, the regulatory mechanisms governing repair proteins involved in this process, including ERCC6, remain incompletely defined. This study was designed to investigate the role of ERCC6 in ER–mitochondrial crosstalk and its post-translational regulation during ARC pathogenesis. Using clinical samples, Emory mutant mice and H₂O₂-treated SRA01/04 cells, we demonstrated that ERCC6 protein levels were significantly reduced in ARC through MDM2-mediated ubiquitination. Co-immunoprecipitation and cycloheximide chase assays revealed that MDM2 directly binds to ERCC6’s ATPase domain, accelerating its proteasomal degradation. Additionally, ERCC6 overexpression inhibited the activation of PERK pathway, mitochondrial Ca²⁺ overload, and apoptosis during oxidative stress, while PERK inhibitor GSK2606414 rescued lens opacity caused by ERCC6 knockdown in ex vivo models. Crucially, MDM2 overexpression reversed ERCC6’s protective effects, confirming the MDM2/ERCC6/PERK axis as a central regulator of LEC survival. These findings not only identify ERCC6 ubiquitination as a novel pathogenic mechanism in ARC but also highlight its therapeutic potential for cataract prevention by targeting oxidative stress-ERS-mitochondrial cascades.</p> Graphical abstract <p></p>