Musk ameliorates acute high-altitude cerebral edema by regulating necroptosis-microglial polarization crosstalk through the HIF-1α/RIPK3 axis.

Musk, a precious animal-derived medicine in traditional Chinese medicine and Tibetan medicine, possesses pungent and warm properties with strong penetrating power. As recorded in Compendium of Materia Medica (Bencao Gangmu), this substance "unblocks all orifices and dredges meridians and collaterals", and has long been widely used in the treatment of coma and loss of consciousness. Modern research demonstrates that musk can excite the central nervous system, enhance hypoxia tolerance, and improve cerebral blood circulation. Both these traditional applications and modern findings provide a theoretical basis for investigating the neuroprotective effect of musk on nervous system disorders such as high-altitude cerebral edema. This study aims to explore the efficacy of musk in the treatment of high-altitude cerebral edema (HACE) and its molecular mechanism. A rat model of HACE under the condition of 6000 m above sea level was established using a low-pressure hypoxic chamber. Brain-penetrating components of musk were identified by UHPLC-MS/MS, and potential targets and pathways were predicted using network pharmacology and transcriptomics. The therapeutic effect of musk was evaluated through methods such as histopathological analysis, TEM, and IF/IHC. The mechanism was further verified by culturing microglia under low-pressure hypoxic conditions. The participation of the HIF-1α/RIPK3 axis was confirmed using M1 polarization inducers (LPS/IFN-γ) and lentivirus-mediated knockdown (shRNA). Musk treatment significantly alleviated brain edema caused by hypobaric hypoxia in rats, reversed pro-inflammatory polarization, and improved the necrotic damage of brain tissue. Network pharmacology and transcriptomics analyses converged on the HIF-1α signaling pathway as the central regulatory hub. In vitro studies further confirmed that musk improved microglia vitality, inhibited the release of inflammatory cytokines and DAMPs, and suppressed necroptosis. Additionally, lentivirus-mediated knockdown of HIF-1α or RIPK3 produced similar effects to those of musk, while the use of M1 polarization inducers weakened these effects, confirming the essential role of the HIF-1α/RIPK3 axis. This study demonstrates that musk regulates the interaction between necroptosis and polarization phenotypes of microglia by acting on the HIF-1α/RIPK3 axis, thereby alleviating cerebral edema at high altitudes. It reveals a novel pathological mechanism of HACE and provides modern scientific evidence for the traditional use of musk in treating high-altitude brain disorders.