Conclusively, this integrative multiomics study highlights the novel pathogenic variants of AKR1D1, LIPC, and SERPINE1 in metabolic, immune, and lipid pathways that are highly expressed among hepatocytes in obese patients while possibly carrying pathogenic mutations that may be associated with NAFLD, emphasizing their potential as novel targets for therapeutic strategies and biomarker development in early diagnosis and treatment before the onset of cirrhosis or hepatocellular carcinoma. This evidence concerns the gene AKR1D1 and metabolic dysfunction-associated steatotic liver disease.