The better overall effect on NAFLD is related to the enhancement of lipolysis and β-oxidation by bicyclol via restoring the p62-Nrf2-CES2/PPARα signaling axis and suppression of lipogenesis by berberine via downregulating ACC and FAS, along with the enrichment of lipid metabolism-related Bacteroidaceae (family) and Bacteroides (genus) by berberine. Here, SQSTM1 is linked to metabolic dysfunction-associated steatotic liver disease.