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

Fangquan Chen, Hu Tang, Changfeng Li, Rui Kang, Daolin Tang () and Jiao Liu ()
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Fangquan Chen: Guangzhou Medical University
Hu Tang: Guangzhou Medical University
Changfeng Li: China-Japan Union Hospital of Jilin University
Rui Kang: UT Southwestern Medical Center
Daolin Tang: UT Southwestern Medical Center
Jiao Liu: Guangzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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, and lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent cell death. We reveal CYP51A1, a gene involved in cholesterol synthesis, as a key suppressor of alkalization-induced cell death in pancreatic cancer cells. Inducing intracellular alkalization by the small molecule JTC801 leads to a decrease in endoplasmic reticulum cholesterol levels, subsequently activating SREBF2, a transcription factor responsible for controlling the expression of genes involved in cholesterol biosynthesis. Specifically, SREBF2-driven upregulation of CYP51A1 prevents cholesterol accumulation within lysosomes, leading to TMEM175-dependent lysosomal proton efflux, ultimately resulting in the inhibition of cell death. In animal models, including xenografts, syngeneic orthotopic, and patient-derived models, the genetic or pharmacological inhibition of CYP51A1 enhances the effectiveness of JTC801 in suppressing pancreatic tumors. These findings demonstrate a role of the CYP51A1-dependent lysosomal pathway in inhibiting alkalization-induced cell death and highlight its potential as a targetable vulnerability in pancreatic cancer.

Date: 2025
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DOI: 10.1038/s41467-025-57583-2

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