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Peer-reviewedCC BYCell biochemistry and function

Lipid Metabolic Reprogramming and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights From Lipidomics

  • Revathi Valliyodu1,2
  • Diya Maria Siril2,3
  • Harsha Sanil1,2
  • Areej Nazarudeen1
  • Aswathy Usha Vijayamoorthy1,4
  • Mahesh Chandran Valiyavilakathuveedu Rajan3,5
  • Sudhina Sufina1,2
  • Chandana Yesudas2
  • Abhirami Nalinakshan1
  • Radhika Achuthan6
  • Muthunayagam Vibin7
  • Janeesh Plakkal Ayyappan1,2,3
7 affiliations
  1. 1Department of Biochemistry University of Kerala, Kariavattom Campus Thiruvananthapuram Kerala India
  2. 2Centre for Advanced Cancer Research, Department of Biochemistry University of Kerala, Kariavattom Campus Thiruvananthapuram Kerala India
  3. 3Department of Biotechnology University of Kerala, Kariavattom Campus Thiruvananthapuram Kerala India
  4. 4CEPCI Laboratory & Research Institute (The Cashew Export Promotion Council of India) Kollam Kerala India
  5. 5DBT‐SAHAJ National Facility for Mass Spectrometry, Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram India
  6. 6Department of Biochemistry Government Arts and Science College, Kulathoor Thiruvananthapuram Kerala India
  7. 7Department of Biochemistry, St. Albert's College (Autonomous) Mahatma Gandhi University Ernakulam Kerala India
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound resistance to chemotherapy that cannot be fully explained by mutational drivers alone. This review examines how lipid metabolic reprogramming contributes to cytotoxic chemotherapy resistance in PDAC and evaluates whether lipidomics and flux‐resolved metabolic analyses can identify functionally relevant therapeutic vulnerabilities. Current evidence on lipid metabolism in PDAC was reviewed, focusing on fatty acid uptake, de novo lipogenesis, desaturation, cholesterol metabolism, lipid droplet dynamics, fatty acid oxidation and ferroptosis regulation. Recent advances in lipidomic technologies, including LC–MS‐based lipidomics, single‐cell lipidomics, spatial lipid profiling and stable isotope tracing, were also evaluated for their ability to characterise metabolic states associated with cytotoxic chemotherapy resistance. PDAC cells resistant to cytotoxic chemotherapy undergo coordinated lipid metabolic rewiring involving enhanced lipid uptake and synthesis, altered fatty acid saturation balance, cholesterol‐rich membrane remodelling and increased lipid storage. These adaptations stabilise membrane architecture, sustain survival signalling, buffer oxidative stress and suppress ferroptosis. Tumour–stroma metabolic coupling further reinforces resistance through lipid exchange and metabolic interactions involving cancer‐associated fibroblasts and immune cells. Emerging lipidomic and flux‐resolved approaches reveal substantial intratumoural heterogeneity and identify lipid‐dependent survival states not captured by genomic or transcriptomic profiling alone. Chemoresistance in PDAC represents a dynamic lipid‐dependent metabolic phenotype driven by membrane remodelling and flux redistribution rather than isolated pathway activation. Integration of lipidomics with spatial and isotope‐resolved analyses may improve therapeutic stratification and support development of combination strategies targeting lipid metabolic vulnerabilities in PDAC.

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Cite

BibTeXRIS
BibTeX
@article{valliyodu2026lipid,
  title = {{Lipid Metabolic Reprogramming and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights From Lipidomics}},
  author = {Revathi Valliyodu and Diya Maria Siril and Harsha Sanil and Areej Nazarudeen and Aswathy Usha Vijayamoorthy and Mahesh Chandran Valiyavilakathuveedu Rajan and Sudhina Sufina and Chandana Yesudas and Abhirami Nalinakshan and Radhika Achuthan and Muthunayagam Vibin and Janeesh Plakkal Ayyappan},
  journal = {Cell biochemistry and function},
  year = {2026},
  month = oct,
  doi = {10.1002/cbf.70333},
  url = {https://europepmc.org/article/PMC/PMC13711320},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Lipid Metabolic Reprogramming and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights From Lipidomics
AU  - Revathi Valliyodu
AU  - Diya Maria Siril
AU  - Harsha Sanil
AU  - Areej Nazarudeen
AU  - Aswathy Usha Vijayamoorthy
AU  - Mahesh Chandran Valiyavilakathuveedu Rajan
AU  - Sudhina Sufina
AU  - Chandana Yesudas
AU  - Abhirami Nalinakshan
AU  - Radhika Achuthan
AU  - Muthunayagam Vibin
AU  - Janeesh Plakkal Ayyappan
PY  - 2026
DA  - 2026/10/01
JO  - Cell biochemistry and function
DO  - 10.1002/cbf.70333
UR  - https://europepmc.org/article/PMC/PMC13711320
AB  - Pancreatic ductal adenocarcinoma (PDAC) exhibits profound resistance to chemotherapy that cannot be fully explained by mutational drivers alone. This review examines how lipid metabolic reprogramming contributes to cytotoxic chemotherapy resistance in PDAC and evaluates whether lipidomics and flux‐resolved metabolic analyses can identify functionally relevant therapeutic vulnerabilities. Current evidence on lipid metabolism in PDAC was reviewed, focusing on fatty acid uptake, de novo lipogenesis, desaturation, cholesterol metabolism, lipid droplet dynamics, fatty acid oxidation and ferroptosis regulation. Recent advances in lipidomic technologies, including LC–MS‐based lipidomics, single‐cell lipidomics, spatial lipid profiling and stable isotope tracing, were also evaluated for their ability to characterise metabolic states associated with cytotoxic chemotherapy resistance. PDAC cells resistant to cytotoxic chemotherapy undergo coordinated lipid metabolic rewiring involving enhanced lipid uptake and synthesis, altered fatty acid saturation balance, cholesterol‐rich membrane remodelling and increased lipid storage. These adaptations stabilise membrane architecture, sustain survival signalling, buffer oxidative stress and suppress ferroptosis. Tumour–stroma metabolic coupling further reinforces resistance through lipid exchange and metabolic interactions involving cancer‐associated fibroblasts and immune cells. Emerging lipidomic and flux‐resolved approaches reveal substantial intratumoural heterogeneity and identify lipid‐dependent survival states not captured by genomic or transcriptomic profiling alone. Chemoresistance in PDAC represents a dynamic lipid‐dependent metabolic phenotype driven by membrane remodelling and flux redistribution rather than isolated pathway activation. Integration of lipidomics with spatial and isotope‐resolved analyses may improve therapeutic stratification and support development of combination strategies targeting lipid metabolic vulnerabilities in PDAC.
SN  - 0263-6484
SN  - 1099-0844
ER  -