Understanding the mechanisms of evasive resistance in cancer is of great importance to develop efficient therapies.Analyzing the Me 4th of July Dress molecular mechanisms underlying therapy resistance of hepatocellular carcinoma (HCC), we have discovered a kinase-activity independent role of LATS1 (large tumor suppressor) but not LATS2 in regulating sorafenib-induced lethal autophagy in HCC.We have found that the autophagy regulatory role of LATS1 is a general phenomenon in response to various stimuli of autophagy induction which relies on Examination a LATS1-specific protein domain.Mechanistically, the autophagy regulatory role of LATS1 is coupled with Beclin-1 (BECN1) K27-linked ubiquitination and BECN1 self-dimerization.Our study highlights a LATS1-mediated non-classical interaction between the Hippo signaling pathway and autophagy in therapy response and carcinogenesis.