Gallic acid’s protective mechanisms against acrylamide-induced pulmonary injury: in vivo and in silico insights into the Nrf-2/HO-1/NFκB pathway modulation

Acrylamide (ACR) is a toxic compound formed during the heating of tobacco and starchy foods, contributing to increased reactive oxygen species (ROS) levels and significant health risks. This study evaluates the protective effects of gallic acid (GA), a natural polyphenol with potent antioxidant and anti-inflammatory properties, against ACR-induced lung injury. Fifty male rats were divided into five groups: Control, ACR, GA50 + ACR, GA100 + ACR, and GA100. Lung tissues were analyzed biochemically, histopathologically, immunohistochemically, and via immunofluorescence. GA exhibited dose-dependent protective effects by enhancing antioxidant defenses through Nrf-2 (43% increase) and HO-1 activation and reducing lipid peroxidation markers (MDA decreased by 38%). GA also suppressed pro-inflammatory mediators (TNF-α reduced by 35%) and restored anti-inflammatory levels by modulating the NF-κB pathway. Furthermore, GA reduced apoptosis (Caspase-3 activity decreased by 30%) and preserved lung tissue integrity by mitigating oxidative DNA damage (8-OHdG levels reduced by 29%) and pro-apoptotic signaling (Bax levels reduced by 34%). Computational analyses demonstrated GA's interaction with the KEAP1 protein, supporting its role in activating the KEAP1-Nrf2 pathway. These findings highlight GA's antioxidant, anti-inflammatory, and anti-apoptotic properties, suggesting its therapeutic potential for protecting against ACR-induced lung injury and paving the way for future research in lung health and toxicology. © The Author(s) 2025.