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

  • Nat Commun. 2025 Mar 7;16(1):2278. doi: 10.1038/s41467-025-57583-2.
Fangquan Chen  1  2 ,  Hu Tang  1  2 ,  Changfeng Li  3 ,  Rui Kang  4 ,  Daolin Tang  5 ,  Jiao Liu  6  7
Affiliations
  • 1. DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 2. Department of Critical Care Medicine, State Key Laboratory of Respiratory Disease, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 3. Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
  • 4. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
  • 5. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 6. DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
  • 7. Department of Critical Care Medicine, State Key Laboratory of Respiratory Disease, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
PMID: 40055353 DOI: 10.1038/s41467-025-57583-2
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.

Products