Paeoniflorin alleviates hypobaric hypoxia-triggered lung injury through targeting MEK2 to modulate ERK2–SGK1 signaling

Hypobaric hypoxia-induced lung injury can exacerbate the incidence of plateau pulmonary edema, but relevant pharmacologic measures are relatively limited. Here, we investigate the possible role of paeoniflorin (Pae) in hypobaric hypoxia-induced lung injury. Through in vivo and in vitro experiments, we observed that Pae significantly ameliorated hypobaric hypoxia-triggered oxidative stress, inflammatory response, mitochondrial dysfunction and ferroptosis. Using limited proteolysis-mass spectrometry (LiP-MS), molecular docking, and molecular dynamics simulations, we identified that Pae directly binds to three amino acid residues (K101, D156, and S198) of the MEK2 protein. Knockdown of MEK2 expression in vivo and in vitro abrogated the protective effect of Pae. It was also observed that Pae promotes the binding of MEK2 and ERK2 and increases the phosphorylation level of ERK2, leading to its activation. This process induced upregulation of SGK1 and the protective effect of Pae against hypobaric hypoxic lung injury was dependent on SGK1. Collectively, these findings provide pharmacological evidence that Pae activates SGK1 by targeting MEK2 and mediating MEK2–ERK2 crosstalk, highlighting Pae’s potential as a promising therapeutic agent for hypoxic lung injury-related diseases. Paeoniflorin targets MEK2 and mediates MEK2–ERK2 interaction to activate SGK1, suppresses excessive opening of the mitochondrial mPTP, improves mitochondrial homeostasis and function, and alleviates oxidative stress and inflammatory responses, consequently attenuating hypobaric hypoxia-induced lung injury.