Fig. 5: Schematic depicting the effects of PIKfyve inhibition and KRAS–MAPK inhibition.
From: Targeting PIKfyve-driven lipid metabolism in pancreatic cancer
Left, with functional PIKfyve and KRAS–MAPK signalling, PDAC is at metabolic homeostasis, able to generate lipids through both de novo synthesis and lysosomal acquisition and recycling processes. Middle, with PIKfyve inhibition, lysosomal functions are disrupted, leading to lysosomal swelling or vacuolization and sequestering of lipids on lysosomal membranes. This leads to a relative decrease in cellular lipid availability, forcing PDAC cells to activate de novo lipid synthesis, activating SREBP and pro-lipogenic transcriptional and metabolic programs. Right, concurrent PIKfyve and KRAS–MAPK inhibition blocks both the lysosomal recycling and acquisition and the de novo synthesis pathways of obtaining lipids, leading to synthetic lethality. Created in BioRender. Cheng, C. (2025) https://BioRender.com/d149928.
