Lathyrol Targets G6PD to Disrupt Redox Homeostasis in Non-Small Cell Lung Cancer

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Lathyrol, a natural compound from Euphorbiaceae plants, shows antitumor potential.
• Its specific molecular targets and mechanisms in non-small cell lung cancer (NSCLC) are not fully understood.

Purpose of the Study:

• To systematically identify lathyrol-binding proteins in NSCLC cells.
• To elucidate the molecular mechanisms underlying lathyrol's antitumor activity.

Main Methods:

• Thermal proteome profiling (TPP) to identify lathyrol-binding proteins.
• Cellular thermal shift assay (CETSA) and peptide-centric local stability assay (PELSA) to validate target engagement.
• Enzymatic assays and quantitative proteomics to assess functional consequences.

Main Results:

• TPP identified glucose-6-phosphate dehydrogenase (G6PD) as a primary lathyrol-binding protein.
• CETSA and PELSA confirmed direct interaction and conformational changes in G6PD.
• Lathyrol treatment reduced G6PD activity, decreased intracellular NADPH, and altered glucose metabolism and redox pathways.

Conclusions:

• G6PD is a functional target of lathyrol in NSCLC.
• Lathyrol inhibits G6PD, disrupting cellular redox balance and metabolic homeostasis.
• These findings provide a mechanistic basis for lathyrol's antitumor effects and suggest G6PD as a therapeutic target.