Melatonin Alleviates Atrazine-Induced Kidney Damage by Regulating RIPK3 to Inhibit Necroptosis

The widely used herbicide atrazine accumulates in renal tissue due to its lipophilicity, posing a significant risk to kidney health. Melatonin, a pineal hormone, has demonstrated renal protective effects, although its precise mechanisms remain elusive. This study investigates the protective role of melatonin against atrazine-induced kidney injury. Using both in vivo and in vitro models, we demonstrated that atrazine exposure triggers TNF-α-mediated activation of the RIPK1–RIPK3–MLKL pathway, leading to renal tubular epithelial cell necroptosis, mitochondrial dysfunction, and inflammatory responses. Melatonin treatment significantly alleviated these effects. Molecular docking and molecular dynamics simulations suggest that melatonin may bind to RIPK3, inhibiting its phosphorylation and subsequent necroptotic signaling. Knockdown of RIPK3 eliminated atrazine-induced damage, confirming that RIPK3 is a key target. These findings elucidate a novel mechanism by which melatonin mitigates atrazine-induced renal injury through the RIPK3-dependent inhibition of necroptosis, highlighting its potential as a therapeutic agent for chemical-induced nephrotoxicity.