RT Journal Article
T1 Redefining the role of hypoxia-inducible factors (HIFs) in oxygen homeostasis
A1 Arias, Clemente F.
A1 Acosta Salmerón, Francisco Javier
A1 Bertocchini, Federica
A1 Fernández Arias, Cristina
AB Hypoxia-inducible factors (HIFs) are key regulators of intracellular oxygen homeostasis. The marked increase in HIFs activity in hypoxia as compared to normoxia, together with their transcriptional control of primary metabolic pathways, motivated the widespread view of HIFs as responsible for the cell’s metabolic adaptation to hypoxic stress. In this work, we suggest that this prevailing model of HIFs regulation is misleading. We propose an alternative model focused on understanding the dynamics of HIFs’ activity within its physiological context. Our model suggests that HIFs would not respond to but rather prevent the onset of hypoxic stress by regulating the traffic of electrons between catabolic substrates and oxygen. The explanatory power of our approach is patent in its interpretation of the Warburg effect, the tendency of tumor cells to favor anaerobic metabolism over respiration, even in fully aerobic conditions. This puzzling behavior is currently considered as an anomalous metabolic deviation. Our model predicts the Warburg effect as the expected homeostatic response of tumor cells to the abnormal increase in metabolic demand that characterizes malignant phenotypes. This alternative perspective prompts a redefinition of HIFs’ function and underscores the need to explicitly consider the cell’s metabolic activity in understanding its responses to changes in oxygen availability.
PB Springer Nature
SN 2399-3642
YR 2025
FD 2025-03-16
LK https://hdl.handle.net/20.500.14352/120433
UL https://hdl.handle.net/20.500.14352/120433
LA eng
NO Arias, C. F., Acosta, F. J., Bertocchini, F., & Fernández-Arias, C. (2025). Redefining the role of hypoxia-inducible factors (HIFs) in oxygen homeostasis. Communications Biology, 8(1). https://doi.org/10.1038/S42003-025-07896-1
NO Cr.F.A. was partially supported by the MINECO grant PID2022-138187OB-I00.
NO Ministerio de Economía y Competitividad (España)
DS Docta Complutense
RD 17 dic 2025