Hypoxia up-regulated 1 (HYOU1) is involved in hepatic steatosis via N6-methyladenosine (m6A)-dependent stabilization and modulation of circadian clock genes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by profound disturbances in hepatic lipid metabolism. However, the role of N6-methyladenosine (m6A)-mediated dysregulation of specific stress-responsive proteins in governing metabolically critical gene expression, particularly the clock system, in this context remains largely unexplored. Notably, there is no prior experimental evidence linking Hypoxia Up-Regulated 1 (HYOU1) to MASLD pathology. Combining bioinformatics with validation, we identify HYOU1 as aberrantly upregulated in MASLD. Elevated HYOU1 promotes upregulation of core clock genes Circadian Locomotor Output Cycles Kaput (CLOCK) and Cryptochrome 1 (CRY1) while suppressing GYS2. Mechanistically, the m6A demethylase Fat mass and obesity-associated protein (FTO) stabilizes HYOU1 mRNA by erasing repressive m6A modifications. Knockdown of HYOU1 alleviates hepatic steatosis and normalizes these clock components. Crucially, rescue experiments show that CLOCK/CRY1 overexpression or GYS2 suppression significantly attenuates the protective benefits of HYOU1 depletion in murine livers. Collectively, our findings define HYOU1 as a novel mediator of MASLD. Targeting the FTO-HYOU1 axis alleviates hepatic steatosis and restores clock gene expression via an indirect regulatory mechanism, highlighting the strategic value of modulating upstream drivers to circumvent the potential risks of directly manipulating core clock machinery. SYNOPSIS: The role of N6-methyladenosine (m6A)-mediated dysregulation of specific stress-responsive proteins in governing metabolically critical genes, such as the clock system, in metabolic dysfunction-associated steatotic liver disease (MASLD) remains largely unexplored, with no prior experimental evidence linking Hypoxia Up-Regulated 1 (HYOU1) to this pathology. This study identifies HYOU1 as a previously unrecognized contributor that is aberrantly upregulated in MASLD in an m6A-dependent manner and functions as a critical modulator of clock genes, thereby promoting hepatic steatosis.