Zinc gluconate attenuates oxaliplatin-induced pulmonary injury via suppressing the TLR4/NF-κB signaling.

Oxaliplatin (OXA), a third-generation platinum-based chemotherapeutic agent widely used to treat solid tumors, has potential pulmonary toxicity whose underlying mechanisms remain poorly understood. This study investigates the role of Toll-like receptor 4 (TLR4) signaling in OXA-induced lung injury and evaluates the protective effects of zinc gluconate (ZG). Using a mouse model of OXA-induced pulmonary toxicity, we observed that OXA administration led to significant pulmonary inflammation, alveolar structural disruption, and fibrotic remodeling, accompanied by upregulation of pro-inflammatory cytokines and extracellular matrix components. TLR4-knockout (KO) mice exhibited markedly attenuated lung injury, reduced inflammatory infiltration, and diminished fibrotic responses compared to wild-type mice, indicating that TLR4 signaling critically mediates OXA-induced pulmonary pathology. In vitro, OXA activated the TLR4/MyD88/NF-κB pathway, promoting inflammatory cytokine production and epithelial-mesenchymal transition (EMT) in BEAS-2B cells. Pharmacological inhibition of TLR4 with resatorvid (Tak242) effectively reversed these effects, further confirming the central role of this pathway. Notably, ZG treatment significantly alleviates OXA-induced lung injury in mice, as evidenced by reduced inflammation, collagen deposition, and EMT. Mechanistically, ZG inhibited OXA-induced activation of the TLR4/NF-κB signaling and restored intracellular zinc levels. However, TLR4 activation by RS09 reversed the protective effect of ZG. Collectively, these findings demonstrate that OXA induces pulmonary injury via TLR4 /NF-κB-dependent inflammatory and fibrosis, and that ZG exerts protective effects by suppressing this signaling. Our study identifies as a promising therapeutic target and highlights ZG as a potential adjunctive strategy for preventing OXA-associated pulmonary toxicity.