El-Sehrawy Amr Ali Mohamed Abdelgawwad, Hsu Chou-Yi, Alkhathami Ali G, Chandra Muktesh, Basunduwah Tina Saeed, Malathi H, Senapati Jitendra Narayan, Gautam Apurav, Kadhem Mundher, Yasin Hatif Abdulrazaq
Internal medicine, Diabetes, Endocrinology and Metabolism, Mansoura University, Mansoura, Egypt.
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan.
Semin Oncol. 2025 Oct;52(5):152392. doi: 10.1016/j.seminoncol.2025.152392. Epub 2025 Jul 16.
Metabolic reprogramming enables stress adaptation of cancer cells to treatment and is a primary causative force of drug resistance. Dysregulation of glucose, amino acid, and lipid metabolism supplies energy, biosynthetic precursors, and redox balance, promoting survival in the treated tumor. These processes are coordinated by oncogenic signaling, loss of tumor suppressors, and regulatory non-coding RNAs, which promote cancer stemness, immune evasion, and resistance to apoptosis. This review examines the mechanisms by which central metabolic pathways, particularly glycolysis, glutamine metabolism, and fatty acid synthesis, are altered to facilitate drug resistance in various types of cancer. Additionally, we report on novel therapeutic approaches that exploit such metabolic weaknesses to prevent therapy resistance and enhance clinical outcomes. Future directions emphasize the need for advanced metabolic profiling to personalize treatment approaches and the clinical translation of promising preclinical findings to overcome this significant obstacle in cancer therapy.
