Autophagy is a major pathway for degradation of dysfunctional organelles and misfolded or aggregated proteins, and its defects trigger oxidative stresses to induce cell death, promote liver fibrosis and HCC, and reduce lifespans. Natural component spermidine enhances autophagy flux by depleting cytosolic histone deacetylase 4 and reducing its interaction with autophagy activator microtubule-associated protein MAP1S to dramatically expand lifespans and to prevent liver fibrosis and hepatocellular carcinomas. For details, see article by Yue and colleagues on page 2938.