Fig. 1: Hypoxia-related mechanisms of sorafenib resistance and targeting strategies against HIFs

Sustained sorafenib treatment enhances hypoxia-inducible factors 1α or 2α, which promote the transcription of a wide range of genes involved in mitophagy, proliferation, glucose metabolism, angiogenesis, tumor invasion, and metastasis, leading to sorafenib resistance. This resistance can be overcome by different small molecules or drugs that inhibit HIFs. ADP, adenosine diphosphate; ATP, adenosine triphosphate; BNIP3, B-cell lymphoma-2 (BCL2)/adenovirus E1B 19 kDa-interacting protein 3; c-Myc, Myc proto-oncogene protein; CoA, coenzyme A; EGFR, phospho-epidermal growth factor receptor; GLUT-1, glucose transporter 1; HIF, hypoxia-inducible factor; HK2, hexokinase 2; LDHA, lactate dehydrogenase A; MDR1, multidrug resistance protein 1; NAD⁺, nicotinamide adenine dinucleotide (oxidized form); NADH, nicotinamide adenine dinucleotide (reduced form); NIX, BNIP3-like protein X; P, phosphate; PCNA, proliferating cell nuclear antigen; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase isoform 1; TGF-α, transforming growth factor α; TIP30, oxidoreductase HTATIP2; VEGF, vascular endothelial growth factor