In this perspective review, we will go through the fundamental concept of chronic inflammation in neurodegenerative diseases and cancer, update the WWOX functional properties in suppressing Alzheimer’s disease (AD) and cancer, and discuss how Zfra peptide regulates AD and cancer via Hyal-2/WWOX/Smad4 signaling and how Z cell activation by Zfra works in limiting disease progression. Here, SMAD4 is linked to cancer.