Lapachol Nanoparticles Mitigate Mercuric Chloride-induced Pulmonary Toxicity via Modulation of Oxidative Stress, Inflammatory Signaling, and Nrf2/P39 Pathways

Abstract

Mercuric chloride (HgCl2) is a common environmental toxicant that causes excessive oxidative stress and inflammation in pulmonary tissue. The present work was designed to evaluate the protective impact of lapachol nanoparticles (LaP-NPs) on HgCl2-induced lung toxicity in mice. LaP-NPs were prepared by nanoprecipitation and characterised for particle size, morphology, and stability. Adult albino mice were divided into six groups: untreated controls; LaP-NPs alone; HgCl2 alone; HgCl2 plus LaP-NPs at two doses (21.5 and 53.75 mg/kg); and HgCl2 plus dexamethasone. All treatments were administered orally for 30 days. Markers of pulmonary oxidative stress (reduced glutathione [GSH], superoxide dismutase [SOD], glutathione peroxidase [GPx], and malondialdehyde [MDA]) and inflammatory cytokines were measured. The gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and protein 39 (P39) were evaluated, and histopathological changes were assessed. Molecular docking was conducted to investigate possible interactions between lapachol and the Nrf2 and P39 protein targets. HgCl2 exposure led to significant oxidative stress, as demonstrated by a significant decline in GSH, SOD and GPx activities along with increased MDA. This was accompanied by strong upregulation of IL-1β (+134.7% in plasma), iNOS (+405%), and MIP-1α (+4248%), as well as robust upregulation of Nrf2 (+570.6%) and P39 (+468.6%) (p < 0.001). High-dose LaPNPs treatment (53.75 mg/kg) significantly reversed the activity of antioxidant enzymes, decreased MDA accumulation, and normalised Nrf2 and P39 expression. Several inflammatory mediators were also significantly suppressed to normal control levels. Histopathological analyses confirmed the biochemical observations, demonstrating preservation of lung architecture. Also, docking simulations showed that lapachol had high predicted binding affinities for both Nrf2 (-8.25 kcal/mol) and P39 (-8.06 kcal/mol). LaP-NPs revealed excellent antioxidant and anti-inflammatory properties, which were superior to those of native lapachol and comparable to dexamethasone. The nanoformulation improved the bioavailability and multiple targeting of lapachol, suggesting a potential protective strategy for heavy-metal-induced lung injury. Limitations are that only one toxicity model was employed. LaP-NPs efficiently prevent HgClⁿ-induced lung injury by inhibiting oxidative stress, modulating stress-related genes, and reducing inflammatory pathways. These findings suggest that LaP-NPs could serve as a nanotherapeutic for heavy metal-induced pulmonary toxicity.