STK38L (also known as NDR2) is a serine/threonine kinase of the Hippo/NDR family that regulates autophagy, cellular organization, and neuronal function. Mechanistically, STK38L functions as a negative autophagy regulator through the TRIM27-STK38L-ULK1 signaling axis 1. Upon K6- and K11-linked ubiquitination by TRIM27, STK38L becomes activated and phosphorylates ULK1 at Ser495, suppressing autophagy amplitude and duration 1. STK38L also regulates mitophagy through ULK1 destabilization and controls osteoclast differentiation via the NDR2/ULK1/mitophagy axis 2. In photoreceptor cells, NDR2 phosphorylates Rabin8 at S272 to regulate rhodopsin trafficking from the Golgi to cilia, with mutations causing hereditary retinal degeneration 3. Clinically, STK38L dysregulation associates with multiple malignancies: elevated STK38L expression correlates with poor pancreatic cancer survival and KRAS-dependency 4, genetic variants in STK38L increase glioma susceptibility 5, and de-SUMOylation-enhanced STK38L activity promotes lung cancer growth through p21 destabilization 6. Loss-of-function mutations cause canine early retinal degeneration affecting photoreceptor development 7. These findings establish STK38L as a multifunctional kinase linking cell survival, proliferation, autophagy, and tissue-specific differentiation.