HACE1 encodes a HECT domain-containing E3 ubiquitin ligase that functions as a tumor suppressor and cellular stress response regulator. The protein plays critical roles in autophagy regulation by ubiquitinating key autophagy components, including ATG5 for K63-linked ubiquitination and proteasomal degradation 1, and PKR for K48-linked polyubiquitination leading to protein degradation 2. HACE1 serves as a bridge between oxidative stress and autophagy, with its expression induced by various stress stimuli to counter cellular damage through promoting antioxidant gene expression and inhibiting ROS production 3. The protein specifically targets GTP-bound RAC1 for ubiquitination and degradation, playing important roles in host defense against pathogens 4. HACE1 also regulates cholesterol metabolism by antagonizing SCAP ubiquitination through competition with other E3 ligases 5. Loss of HACE1 function is associated with multiple diseases, including hereditary spastic paraplegia caused by gene variants 6, and contributes to cancer progression and chemoresistance 7. The protein's involvement in neurodegenerative diseases occurs through its regulation of oxidative stress, autophagy, and inflammation pathways 4.