HypoxamicroRNA-210 protects against hepatic steatosis by inhibiting CIDEC expression

Abstract

Background and AimsMetabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health burden. Although hypoxia is known to contribute to MASLD pathogenesis, the role of hypoxia signaling remains poorly defined. We investigated whether HypoxamicroRNA-210 (miR-210), a key hypoxia-inducible microRNA, regulates hepatic lipid metabolism and MASLD development. MethodsSerum miR-210 levels were quantified in MASLD patients and matched controls. Human hepatic spheroids and HepG2 cells were exposed to fatty acids to assess miR-210 induction and lipid accumulation. miR-210 knockout mice were fed a Western diet to evaluate hepatic steatosis and transcriptomic changes using RNA sequencing. RNA pull-down and 3UTR-driven luciferase reporter assays were employed to identify miR-210 targets. Functional effects of miR-210 mimic were examined in knockout mice, db/db mice, and in vitro human hepatic spheroid models. ResultsSerum miR-210 levels were significantly reduced in MASLD patients compared with matched controls. Consistently, human hepatic spheroids did not appropriately increase miR-210 expression in response to fatty acid-induced intracellular hypoxia. This blunted miR-210 response contributed to hepatic lipid accumulation, as loss of miR-210 in a mouse model of MASLD led to increased hepatic lipid deposition and activation of lipid metabolic pathways. We identified CIDEC as a direct miR-210 target mediating its inhibitory effects on hepatic lipid accumulation, and restoring miR-210 expression suppressed CIDEC and reduced hepatic lipid content in knockout mice on a Western diet. Moreover, miR-210 attenuated lipid accumulation in both in vitro human hepatic spheroids and in vivo db/db mice models of MASLD. ConclusionsmiR-210 protects against hepatic steatosis by inhibiting CIDEC expression, suggesting miR-210-CIDEC axis as a promising therapeutic target for reducing hepatic lipid accumulation and preventing MASLD progression. Impact and ImplicationsThis study addresses a critical gap in understanding how hypoxia signaling shapes MASLD and uncovers a novel pathogenic mechanism of hepatic steatosis arising from fatty acids-induced dysregulation of miR-210. Impaired hypoxia responses, via blunted miR-210 induction, contribute to hepatic lipid accumulation through upregulation of CIDEC, a newly identified target of miR-210. These findings establish miR-210 as a novel regulator of hepatic lipid homeostasis and underscore its therapeutic potential. Interventions aimed at restoring miR-210 function in the liver may offer a promising strategy to ameliorate hepatic steatosis and prevent MASLD progression.