Pterostilbene protects against H2O2‐induced oxidative stress by regulating GAS6/Axl signaling in HL‐1 cells

Pterostilbene (PTE, trans‐3,5‐dimethoxy‐4′‐hydroxystilbene), a natural plant polyphenol, possesses numerous pharmacological effects, including antioxidant, antidiabetic, antiatherosclerotic, and neuroprotective aspects. This study aims to investigate whether PTE plays a protective role against oxidative stress injury by GAS6/Axl signaling pathway in cardiomyocytes. Hydrogen peroxide (H2O2)‐induced oxidative stress HL‐1 cells were used as models. The mechanism by which PTE protected oxidative stress is investigated by combining cell viability, cell ROS levels, apoptosis assay, molecular docking, quantitative real‐time PCR, and western blot analysis. GAS6 shRNA was performed to investigate the involvement of GAS6/Axl pathways in PTE's protective role. The results showed that PTE treatment improved the cell morphology and viability, and inhibited the apoptosis rate and ROS levels in H2O2‐injured HL‐1 cells. Particularly, PTE treatment upregulated the levels of GAS6, Axl, and markers related to oxidative stress, apoptosis, and mitochondrial function related. Molecular docking showed that PTE and GAS6 have good binding ability. Taken together, PTE plays a protective role against oxidative stress injury through inhibiting oxidative stress and apoptosis and improving mitochondrial function. Particularly, GAS6/Axl axis is the surprisingly prominent in the PTE‐mediated pleiotropic effects. Significance statement Oxidative stress causes detrimental effects on cellular components, further promoting the generation of free radicals and intracellular oxidative stress. Pterostilbene (PTE) is a natural plant polyphenol, and has a variety of pharmacological effects. In this study, we proved in vitro evidence of the cardioprotective effects of PTE against oxidative stress injury, primarily through inhibiting oxidative stress and apoptosis and improving mitochondrial function. Furthermore, GAS6/Axl axis is the surprisingly prominent in the PTE‐mediated pleiotropic effects.