The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network

ABSTRACT: MLKL, as the executor of necroptosis and a critical factor in the inflammation, has been shown to be associated with the progression of hemorrhagic stroke. Studies identified MLKL is a promoting factor in this process, suggesting its potential as a therapeutic target to mitigate post-hemorrhagic stroke damage. However, there is no direct evidence supporting MLKL as a drug target for hemorrhagic stroke currently, and the precise mechanisms by which MLKL functions in this context remain unclear. Here, we established an intracerebral hemorrhage model by collagenase IV injection and found that MLKL knockout alone was insufficient to fully reverse neuroinflammation and pathological damage. To further elucidate the molecular mechanisms underlying the effects of MLKL knockout on the ICH model, we conducted a proteomic analysis via LC-MS/MS. While MLKL knockout did not significantly reverse the damage caused by intracerebral hemorrhage, enhanced pathways related to inflammation, metabolism, and coagulation as well as attenuated functions related to neuron assemble were identified, suggesting that MLKL may exert its effects through these pathways. Based on these findings, we hypothesize that co-targeting MLKL and its associated protein network may yield better therapeutic outcomes for hemorrhagic stroke.

ORGANISM(S): Mus Musculus

SUBMITTER: Jingbo Qie  

PROVIDER: PXD056595 | iProX | Fri Sep 27 00:00:00 BST 2024

REPOSITORIES: iProX