Age-related macular degeneration (AMD) is a leading cause of blindness in older adults and is closely linked to dysfunction of the retinal pigment epithelium (RPE). Arsenic (As), a ubiquitous environmental toxicant present in drinking water and food, has been implicated in multiple chronic diseases. However, its role in AMD remains unclear. This study aimed to investigate the effects of As exposure on AMD-related retinal injury and to elucidate the underlying molecular mechanisms using in vitro and in vivo experimental models. ARPE-19 cells were treated with sodium iodate (NaIO) to establish an AMD-like injury model and then exposed to 1 µM As to assess cell viability, apoptosis, oxidative stress, mitochondrial dysfunction, autophagy-related changes and epithelial barrier integrity. Evaluation of NF-κB signaling pathway activation using molecular biology techniques. In vivo, a NaIO-induced mouse model of AMD was established and combined with As exposure at 25 ppm to to validate retinal damage, oxidative stress, mitochondrial impairment, and barrier dysfunction. ShRNA-mediated silencing of NF-κB was further used to confirm pathway involvement. As exposure significantly aggravated NaIO-induced injury in ARPE-19 cells and mouse retinas. In vitro, As reduced cell viability and enhanced apoptosis, inflammatory responses, reactive oxygen species accumulation, mitochondrial dysfunction, autophagy dysregulation, and epithelial barrier disruption. In vivo, As exacerbated retinal structural damage, increased oxidative stress, impaired mitochondrial function, and further reduced the expression of tight junction proteins in NaIO-treated mice. Mechanistically, these effects were accompanied by sustained activation of the NF-κB signaling pathway. ShRNA-mediated silencing of NF-κB partially reversed As-induced retinal damage in vivo. Our study found that As exposure exacerbated AMD-like retinal degeneration via NF-κB pathway. These findings identified As as a potentially modifiable environmental risk factor for AMD and suggested that individuals in As-endemic regions may benefit from targeted retinal screening. Moreover, NF-κB pathway targets inhibition emerged as a candidate strategy for mitigating As-exacerbated retinal injury. 3 3 3 3
