BACKGROUND: Despite the insights into the role of aldehyde dehydrogenase 1 family member A1 (ALDH1A1) in various liver diseases, the expression and its prognostic significance in patients with hepatitis E virus-related acute liver failure (HEV-ALF) remain unclear. This study delved into the assessment of serum exosome-derived ALDH1A1 expression and its prognostic implications for HEV-ALF patients. METHODS: Between January 2018 and December 2023, a total of 226 individuals with acute hepatitis E (AHE) and 210 patients with HEV-ALF were recruited from member units of Chinese Consortium for the Study of Hepatitis E. According to the number of organ failure, we categorized 210 HEV-ALF patients into three groups: two organs failure (n = 131), three organs failure (n = 46), and more than three organs failure (n = 33). In addition, 200 health controls from Suzhou Municipal Hospital were included. RESULTS: The levels of serum exosome-derived ALDH1A1 in HEV-ALF patients were significantly higher than those in AHE patients and health controls (both P <
0.05). Furthermore, the levels of serum exosome-derived ALDH1A1 were the highest in more than three organs failure group, followed by three organs failure group and two organs failure group (all P <
0.001). Moreover, serum exosome-derived ALDH1A1 was positively correlated with total bilirubin in HEV-ALF patients (r = 0.315, P <
0.001). The comparisons of serum exosome-derived ALDH1A1 levels in treatment response showed that serum exosome-derived ALDH1A1 levels were decreased in the improvement group, while increased in the fluctuation and deterioration groups (all P <
0.001). Moreover, serum exosome-derived ALDH1A1 was an independent risk factor for predicting the 30-day mortality (P <
0.001). Furthermore, the area under the receiver operating characteristic curve was 0.943, with the sensitivity of 94.87% and specificity of 87.72%, indicating the robust decision-making ability. However, no significant differences were found in serum exosome-derived ALDH1A1 levels between patients aged <
60 and ≥ 60 years old (P = 0.131). CONCLUSIONS: Serum exosome-derived ALDH1A1 can greatly predict the prognosis of HEV-ALF patients.