OAF Blocks SIAH1‐Mediated Degradation of SCPX, a Therapeutic Strategy for MASLD

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) poses an increasing threat to global public health. Currently approved drugs for MASLD, such as resmetirom and semaglutide, have demonstrated clinical efficacy. However, their use is associated with notable adverse effects, including serious gastrointestinal reactions, metabolic and nutritional disturbances, and renal or urinary system disorders. The present study established that the expression levels of a liver-secreted protein, the "out at first homolog" (Oaf) gene product, are closely associated with metabolic disorders in humans and mice. In a high-fat diet (HD) feeding mouse model, Oaf-deficiency exacerbated hepatic lipid accumulation, whereas intraperitoneal injection of OAF protein ameliorated the development of MASLD. Mechanistically, OAF binds to SCPX and acts as a chaperone, preventing SCPX from degradation by SIAH1-mediated ubiquitination. This stabilizes SCPX and increases its abundance, thereby enhancing cholesterol transport, lipid esterification, and lipid excretion, while inhibiting lipid biosynthesis. In mice, deficiency of either Oaf or Scpx reduced these effects. Collectively, our findings identify OAF as a novel therapeutic target for the treatment of MASLD and provide a rationale for further drug development targeting human fatty liver diseases.