Knockdown of RASD1 improves MASLD progression by inhibiting the PI3K/AKT/mTOR pathway.

Background: There is still no reliable therapeutic targets and effective pharmacotherapy for metabolic dysfunction-associated steatotic liver disease (MASLD). RASD1 is short for Ras-related dexamethasone-induced 1, a pivotal factor in various metabolism processes of Human. However, the role of RASD1 remains poorly illustrated in MASLD. Therefore, we designed a study to elucidate how RASD1 could impact on MASLD as well as the mechanisms involved.

Methods: The expression level of RASD1 was validated in MASLD. Lipid metabolism and its underlying mechanism were investigated in hepatocytes and mice with either overexpression or knockdown of RASD1.

Results: Hepatic RASD1 expression was upregulated in MASLD. Lipid deposition was significantly reduced in RASD1-knockdown hepatocytes and mice, accompanied by a marked downregulation of key genes in the signaling pathway of de novo lipogenesis. Conversely, RASD1 overexpression in hepatocytes had the opposite effect. Mechanistically, RASD1 regulated lipid metabolism in MASLD through the PI3K/AKT/mTOR signaling pathway.

Conclusions: We discovered a novel role of RASD1 in MASLD by regulating lipogenesis via the PI3K/AKT/mTOR pathway, thereby identifying a potential treatment target for MASLD.