CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 7, 2025

Disrupted pH homeostasis can precipitate cell death and represents a viable therapeutic target in oncological interventions. Here, we utilize mass spectrometry-based drug analysis, transcriptomic screens, lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent death. We reveal CYP51A1, gene involved cholesterol synthesis, as key suppressor of alkalization-induced pancreatic cancer cells. Inducing intracellular alkalization by small molecule JTC801 leads decrease endoplasmic reticulum levels, subsequently activating SREBF2, transcription factor responsible for controlling expression genes biosynthesis. Specifically, SREBF2-driven upregulation CYP51A1 prevents accumulation within lysosomes, leading TMEM175-dependent lysosomal proton efflux, ultimately resulting inhibition In animal models, including xenografts, syngeneic orthotopic, patient-derived genetic or pharmacological enhances effectiveness suppressing tumors. These findings demonstrate role CYP51A1-dependent pathway inhibiting highlight its potential targetable vulnerability cancer. Previously, opioid analgesic JCT801 was reported induce via disruption authors investigate JCT801-induced death, identifying synthesis gene,

Language: Английский

Glutathione Metabolism in Ferroptosis and Cancer Therapy

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217697 - 217697

Published: April 1, 2025

Language: Английский

Cytosolic cytochrome c represses ferroptosis

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский