Hypoxia-inducible factors in the immunometabolism of metabolic dysfunction-associated steatotic liver disease (MASLD): molecular mechanisms and therapeutic implications

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a predominant cause of liver disease globally, primarily due to the rising prevalence of metabolic disorders, including obesity and diabetes. The advancement of MASLD from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis involves intricate metabolic and immune interactions. Hypoxia-Inducible Factors (HIFs) are integral to the regulation of cellular responses under hypoxic conditions, significantly influencing metabolic homeostasis and modulating immune cell functions. Within the framework of MASLD, HIFs facilitate the adaptive responses to hypoxic conditions and oxidative stress, which are pivotal drivers of disease progression. However, the precise mechanisms by which HIFs influence MASLD pathogenesis remain incompletely understood. This study seeks to investigate the role of HIFs in the immunometabolic processes of MASLD, with particular emphasis on the molecular pathways they regulate within hepatic cells and the immune microenvironment. Furthermore, we examine the challenges associated with therapeutically targeting HIFs, such as the intricate regulation of HIFs, their tissue-specific effects, and the potential risk of inducing tumorigenesis. In conclusion, we underscore prospective research avenues that may yield innovative therapeutic strategies aimed at targeting HIFs to alleviate inflammation, fibrosis, and metabolic dysregulation in MASLD.