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Alzheimer’s disease (AD) is a degenerative cognition-declining disease with no clear understanding of the underlying mechanisms. Currently, no effective therapeutics are available for AD. Amyloid-β (A-β) plaques and tau tangles were considered as the contributing factors to the development of AD. In contrast, controversial exists due to efforts focusing on A-β as a pharmacological therapeutic target was failed. Emerging evidence appeared for the external stimuli applied through vision (LED) and hearing (~40Hz) to certain intensity to dementia subjects with promising results such as reducing A-β and tau tangles in the brain tissue, increasing the brain volume reducing the decline of daily activities and mental status. This optogenetic and sound-derived digital therapeutic maneuver provides a striking way for conquering the development of AD.

While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multi-omics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Amongst oncologic ROS, hydrogen peroxide specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine gamma lyase (CTH), which converts cystathionine to the non-essential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo . Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target., Competing Interests: The authors have declared that no conflict of interest exists.