PBX1 attenuates MeHg-induced apoptosis by reducing ROS accumulation, mitigating double-strand DNA breaks, and enhancing homologous recombination DNA repair in SH-SY5Y cells.

Methylmercury (MeHg), a highly neurotoxic organic heavy metal, penetrates the central nervous system to induce oxidative damage and DNA double-strand breaks (DSBs). Ascorbic acid mitigates MeHg-mediated oxidative stress in SH-SY5Y cells but fails to repair DSBs via homologous recombination (HR), leaving genotoxicity risks. Pre-B-cell leukemia homeobox 1 (PBX1), a pioneer transcription factor, is reported to alleviate oxidative stress and DSBs while promoting HR-dependent DSB repair. Here, we hypothesized that PBX1 protects SH-SY5Y cells against MeHg-induced injury by suppressing oxidative stress and facilitating HR repair. MeHg reduced PBX1 expression in a time- and dose-dependent manner, accompanied by increased reactive oxygen species (ROS), apoptosis, and non-homologous end joining (NHEJ)-related protein levels, as well as diminished HR activity. PBX1 overexpression reversed these effects, reduced MeHg-induced DNA damage, and enhanced BRCA1 promoter activity. Collectively, PBX1 attenuates MeHg-induced apoptosis in SH-SY5Y cells by inhibiting ROS accumulation, reducing DSBs, and enhancing HR repair, likely via BRCA1 activation.