The ameliorative effects of ginger against heat-induced oxidative stress and mitochondrial dysfunction in Caenorhabditis elegans

Ginger, rich in gingerols and shogaols, exhibits multiple biological properties. However, the mechanisms underlying its thermotolerance remain unclear. The study employed network pharmacology and experimental validation in Caenorhabditis elegans to investigate how gingerol-related compounds within ginger extract (GE) mitigated damage caused by heat stress (HS). A total of 18 types of gingerol analogues were identified in GE, among which 6-, 8-, and 10-gingerol, as well as 6-, 8-, and 10-shogaol were quantified. Collectively, these 6 compounds accounted for 54.4% of the total composition. Supplementation with 15 μg/mL GE significantly extended heat-stress lifespan by 20.30%, while the combination of the 6 major gingerols and shogaols at the same concentration prolonged lifespan by 18.93%. Additionally, pretreatment with GE and the combination alleviated HS-induced oxidative damage by eliminating reactive oxygen species (ROS) and upregulating antioxidant enzymes. Network pharmacology analysis suggested that the MAPK pathway may play a crucial role in thermotolerance. Experimental findings confirmed that ginger attenuated oxidative damage through the activation of SKN-1/Nrf2 and DAF-16/FOXO via the MAPK pathway. Moreover, GE stabilized mitochondrial membrane potential and restored ATP levels, thus preserving mitochondrial function during heat exposure. Further investigations using molecular docking and molecular dynamics simulations revealed that shogaols, with more stable binding affinities for Keap1 protein, exhibited more potent effects than gingerols in prolonging lifespan and reducing ROS levels under HS conditions. In short, gingerol analogues from ginger conferred thermal resistance to nematodes by mitigating oxidative damage and mitochondrial dysfunction.