α7-nAChR activation mitigates pyridaben-induced hepatotoxicity in grass carp (Ctenopharyngodon idella) via SIRT3 restoration and NF-κB/NLRP3 pathway inhibition.

Pyridaben (PDB), a widely used contact acaricide in agriculture and horticulture, is frequently detected in surface waters, where it poses considerable risks to aquatic organisms. α7 nicotinic acetylcholine receptor (α7 nAChR) activation has been shown to mitigate chronic inflammation in many animal models. However, the molecular mechanisms underlying PDB-induced hepatotoxicity and the potential protective effects of α7 nAChR activation remain incompletely understood. This study demonstrates that PDB exposure induces marked hepatotoxicity in grass carp, as evidenced by distinct histopathological alterations including cytoplasmic vacuolization, karyolysis, and hepatocellular steatosis, along with significantly elevated activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which increased by 24.2% and 43.3%, respectively. In contrast, the pathological alterations were effectively mitigated through α7-nAChR activation, which concurrently alleviated oxidative stress, mitochondrial structural damage, and respiratory chain complex (I-V) dysfunction. The anti-inflammatory effects of α7-nAChR activation were demonstrated through suppression of the nuclear factor-κB (NF-κB)/nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) signaling pathway. Molecular docking analysis identified stable hydrophobic interactions in the PDB-SIRT3 complex, evidenced by a binding free energy of -7.252 kcal/mol, concomitant with reduced SIRT3 expression. Furthermore, α7-nAChR activation significantly attenuated hepatic apoptosis via SIRT3 expression restoration. These findings collectively indicate that α7-nAChR-mediated signaling represents a promising therapeutic approach for mitigating PDB-induced hepatotoxicity in aquatic species, providing novel mechanistic insights into its protective functions.