α-Lipoic Acid Activates the Nrf2/HO-1 Pathway to Ameliorate Arsenic-Induced Multiorgan Oxidative Damage

α-Lipoic acid (α-LA) is a natural dietary antioxidant with metal-chelating properties. Inorganic arsenic, a prevalent environmental contaminant in agricultural products, induces systemic oxidative damage upon chronic exposure. However, whether α-LA mitigates arsenic-induced multiorgan toxicity and its underlying mechanisms remain unclear. This study integrated network analysis with in vivo and in vitro validation to investigate this issue. Our results showed that α-LA significantly enhanced systemic antioxidant defenses and alleviated arsenic-induced damage in multiple organs, particularly the liver and kidneys. Mechanistically, α-LA promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent upregulation of heme oxygenase-1 (HO-1). Importantly, siRNA-mediated knockdown of Nrf2 significantly inhibited the protective effects of α-LA. These findings reveal that α-LA counteracts arsenic-induced multiorgan oxidative damage by activating the Nrf2/HO-1 signaling axis, highlighting its potential as an intervention for populations exposed to agricultural arsenic and warranting further clinical investigation.