High altitude pulmonary edema (HAPE) is a potentially fatal condition induced by exposure to high-altitude environment. Eleutheroside B is a naturally active polyphenolic substance that has previously demonstrated anti-inflammatory, antioxidant and antidepressant properties. However, the effects of eleutheroside B on HPAE are unknown. Here, eleutheroside B (50 mg/kg and 100 mg/kg) was applied to HAPE rats. Eleutheroside B alleviated lung edema and decreased levels of tumor necrosis factor-α, interleukin-1β, vascular endothelial growth factor, and total proteins in the bronchoalveolar lavage fluid. Eleutheroside B reversed the acid-base disturbances by HAPE. In addition, eleutheroside B reversed the oxidative stress. Eleutheroside B pretreatment facilitated the translocation of nuclear factor E2-related factor 2 (Nrf2) into the nucleus, contributing to the inhibition of ferroptosis and necroptosis. ML385 confirmed the role of Nrf2 in ferroptosis and necroptosis. Collectively, the beneficial effects of eleutheroside B against HAPE were associated with the inhibition of ferroptosis and necroptosis through Nrf2-antioxidant response signaling.

High-altitude myocardial injury (HAMI) represents a critical form of altitude illness for which effective drug therapies are generally lacking. Notoginsenoside R1, a prominent constituent derived from Panax notoginseng, has demonstrated various cardioprotective properties in models of myocardial ischemia/reperfusion injury, sepsis-induced cardiomyopathy, cardiac fibrosis, and myocardial injury. The potential utility of notoginsenoside R1 in the management of HAMI warrants prompt investigation. Following the successful construction of a HAMI model, a series of experimental analyses were conducted to assess the effects of notoginsenoside R1 at dosages of 50 mg/Kg and 100 mg/Kg. The results indicated that notoginsenoside R1 exhibited protective effects against hypoxic injury by reducing levels of CK, CK-MB, LDH, and BNP, leading to improved cardiac function and decreased incidence of arrhythmias. Furthermore, notoginsenoside R1 was found to enhance Nrf2 nuclear translocation, subsequently regulating the SLC7A11/GPX4/HO-1 pathway and iron metabolism to mitigate ferroptosis, thereby mitigating cardiac inflammation and oxidative stress induced by high-altitude conditions. In addition, the application of ML385 has confirmed the involvement of Nrf2 nuclear translocation in the therapeutic approach to HAMI. Collectively, the advantageous impacts of notoginsenoside R1 on HAMI have been linked to the suppression of ferroptosis via Nrf2 nuclear translocation signaling.