14-Deoxy-11,12-didehydroandrographolide Attenuates Lipotoxicity and Non-Alcoholic Steatohepatitis Through Restoration of Autophagy and Reduction in Oxidative Stress

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder that can progress to non-alcoholic steatohepatitis (NASH), in which lipotoxicity, oxidative stress, apoptosis, and impaired autophagy contribute to liver injury. 14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive diterpenoid from Andrographis paniculata, has shown anti-inflammatory and antioxidant activities, but its role in NASH-associated lipotoxicity remains unclear. This study investigated the protective effects and underlying mechanisms of deAND using palmitic acid (PA)-treated AML12 hepatocytes and a choline-deficient, L-amino acid-defined, high-fat-diet (CDAHFD)-induced mouse model of NASH. In AML12 cells, PA impaired autophagic flux and reduced the expression of the mitophagy-associated proteins PINK1 and Parkin and increased p62, LC3-II, reactive oxygen species production, and apoptotic signaling. deAND treatment restored autophagic flux and increased PINK1 and Parkin expression, enhanced antioxidant defense-related proteins, including HO-1, GCLM, and GPX2, and reduced oxidative stress and apoptosis. The protective effects of deAND were attenuated by autophagy inhibitors, supporting the involvement of autophagy regulation. In CDAHFD-fed mice, deAND reduced hepatic steatosis, inflammation, fibrosis, apoptosis, and autophagy dysregulation. These findings suggest that deAND alleviates lipotoxic liver injury by restoring autophagic homeostasis and reducing oxidative stress.