ArticleNature communications2025
CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- "Alkaline-Hammer Strategy" Breaks Acidic and Stromal Barriers to Induce Alkaliptosis and Enhance Immunotherapy in Pancreatic Cancer.Angewandte Chemie (International ed. in English) · 2026Article
- Localized Intratumoral Ammonium Hydroxide Administration Demonstrates Changes in Tumor Architecture and Renal Response in a Murine Breast Cancer Xenograft Model.Current issues in molecular biology · 2026Article
- Compartmental pH regulation in cancer and antitumor immunity: therapeutic opportunities and challenges.Apoptosis : an international journal on programmed cell death · 2026Review
- Cellular architecture and neighborhood-informed virtual spatial tumor profiling from histopathology.Cell · 2026Article
- TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation.Acta pharmacologica Sinica · 2026Article
- Immune Checkpoint Inhibitors and Immunomodulators for Cancer Immunotherapy: Insights Into Resistance and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- DAMP signaling networks: from receptors to diverse pathophysiological functions.Journal of advanced research · 2026Review
- Review
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- SREBP2-RAB11A-ZDHHC20 axis orchestrates FGFR3 palmitoylation and membrane retention to drive bladder cancer progression.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- CDC26 facilitates ferroptosis through SLC7A11 degradation and cell cycle arrest.Clinical and experimental medicine · 2025Article
- Targeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Metabolic reprogramming promotes apoptosis resistance in acute lymphoblastic leukemia through CASP3 lactylation.Molecular cancer · 2025Article
- CYP51A1 in health and disease: from sterol metabolism to regulated cell death.Cell death discovery · 2025Review
- Blocking cholesterol biosynthesis to clean out cancer.Nature reviews. Cancer · 2025Article
- Cryptotanshinone differentially induces cell death inCancer drug resistance (Alhambra, Calif.) · 2025Article
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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