Genome-Wide CRISPR/Cas9 Screening Reveals Lipid Metabolism and Inflammatory Signalling as Modulators of Ganoderic Acid DM Cytotoxicity
Abdullah, N.; Lewis, J.; Arumugam, P.
Show abstract
Ganoderic Acid DM (GA-DM), a triterpenoid derived from Ganoderma lucidum, exhibits anti-cancer and anti-diabetic activities, but the underlying mechanisms of action remain unclear. To identify genetic modulators of GA-DM response, we conducted a genome-wide CRISPR/Cas9 knockout screen in human melanoma cells. The screen revealed key roles for genes regulating lipid metabolism and inflammatory signalling, particularly the SREBP (Sterol Regulatory Element-binding Protein) and NF-{kappa}B (Nuclear Factor kappa-light-chain-enhancer of activated B cells) pathways, in the cellular response to GA-DM. While loss of genes involved in regulation of cholesterol biosynthesis conferred resistance to GA-DM, the disruption of ubiquitin-mediated proteolysis and the Hippo pathway genes sensitised cells to GA-DM. Inflammatory genes enriched at later time points suggests that a delayed cellular response contributes to cytotoxicity. Our findings propose a mechanistic model wherein GA-DM perturbs lipid and inflammatory pathways to exert cytotoxic effects and highlights potential targets to enhance its therapeutic efficacy. This work demonstrates the utility of functional genomics in elucidating natural product mechanisms and guiding rational drug development.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Parallel CRISPR-Cas9 screens clarify impacts of p53 on screen performance 94%
- Large-scale Phenotypic Drug Screen Identifies Neuroprotectants in Zebrafish and Mouse Models of Retinitis Pigmentosa 94%
- Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline 94%
Similar papers in this journal
- DRUG-seq Provides Unbiased Biological Activity Readouts for Drug Discovery 92%
- A Yeast-Based High-Throughput Screening Platform for the Discovery of Novel pre-mRNA Splicing Modulators 92%
- Development of a new DHFR-based destabilizing domain with enhanced basal turnover and applicability in mammalian systems 91%
Similar papers in this journal
- Oral Hsp90 inhibitor, SNX-5422, attenuates SARS-CoV-2 replication and dampens inflammation in airway cells. 93%
- Drug repurposing reveals Posaconazole as a CYP11A1 inhibitor enhancing anti-tumour immunity 93%
- Drosophila RASopathy Models Identify Disease Subtype Differences and Biomarkers of Drug Efficacy 93%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.