Orm1 protects steatotic livers against ischaemia‑reperfusion injury by stabilising Prdx1 and activating the Pi3k/Akt axis

The clinical utilization of steatotic donor livers is constrained by their marked sensitivity to ischemia/reperfusion (I/R) injury. In the present, Orosomucoid 1 (Orm1) was identify as a pivotal endogenous guardian against steatosis‑associated hepatic I/R damage. Transcriptomic profiling of steatotic livers following I/R identified 1,551 differentially expressed genes, revealing a significant induction of Orm1. Functionally, adenovirus‑mediated knockdown of Orm1 in high‑fat diet fed mice markedly exacerbated I/R‑induced liver injury, evidenced by significant elevations in serum ALT and AST (>2‑fold increase), along with increased hepatocellular necrosis and apoptosis. Conversely, Orm1 overexpression in a palmitic acid and oleic acid‑induced steatotic hepatocyte model effectively reduced reactive oxygen species production and rescued cells from hypoxia/reoxygenation‑induced death (improving viability by 35%). Mechanistically, RNA‑sequencing analysis of Orm1‑knockdown livers identified 3,327 differentially expressed genes highly enriched in the PI3K/Akt pathway. Integrated immunoprecipitation‑mass spectrometry and Co‑immunoprecipitation assays demonstrated that Orm1 interacts with Peroxiredoxin 1 (Prdx1). In addition, it was demonstrated that Orm1 functions as a molecular stabilizer of Prdx1 by protecting it from ubiquitin‑proteasomal degradation, which in turn sustains the activation of the PI3K/Akt survival axis. Pharmacological blockade of Prdx1 or inhibition of Akt significantly reversed Orm1‑mediated hepatoprotection. In conclusion, the present findings delineate the Orm1‑Prdx1‑PI3K/Akt axis as a novel regulatory mechanism in steatotic liver I/R injury, providing a promising mechanistic basis for future therapeutic development.