Acute liver failure (ALF) is a life-threatening disorder. The etiologies of ALF are multifactorial, including drugs or toxins, infections, as well as indeterminate hepatitis [1], [2], [3]. Specifying the cause of ALF has clinical importance because certain causes have better prognosis in several cases without transplantation [4]. In our previous multicenter investigation, higher mortality rate was observed in patients with indeterminate ALF, irrespective of children or adults [5], [6]. In 2022, an epidemic of acute severe hepatitis of unknown etiology causing ALF in children drew attention to the lack of knowledge regarding the pathogenesis of ALF [7]. Therefore, in-depth research into ALF with indeterminate cause possesses great importance.

With the advancement of next-generation sequencing technology, identification of specific mutations in the human genome becomes feasible [8]. In our previous studies regarding ALF, limited by the technology, whole-exome sequencing (WES) was not performed for ALF cases with indeterminate cause. With the aim of providing improved knowledge about indeterminate ALF, we designed the present study to reevaluate its pathogenesis using WES.