Matrine suppresses KRAS‐driven pancreatic cancer growth by inhibiting autophagy‐mediated energy metabolism

Matrine is a natural compound extracted from the herb Sophora flavescens Ait which is widely used in traditional Chinese medicine for treating various diseases. Recently, matrine was reported to have antitumor effects against a variety of cancers without any obvious side effects; however, the molecular mechanisms of its antiproliferative effects on cancer are unclear. Here, we report that matrine inhibits autophagy‐mediated energy metabolism, which is necessary for pancreatic cancer growth. We found that matrine significantly reduces pancreatic cancer growth in vitro and in vivo by insufficiently maintaining mitochondrial metabolic function and energy level. We also found that either pyruvate or α‐ketoglutarate supplementation markedly rescues pancreatic cancer cell growth following matrine treatment. Inhibition of mitochondrial energy production results from matrine‐mediated autophagy inhibition by impairing the function of lysosomal protease. Matrine‐mediated autophagy inhibition requires stat3 downregulation. Furthermore, we found that the antitumor effect of matrine on pancreatic cancer growth depends on the mutation of the KRAS oncogene. Together, our data suggest that matrine can suppress the growth of KRAS‐mutant pancreatic cancer by inhibiting autophagy‐mediated energy metabolism. In this study, we demonstrate for the first time inhibitory effect of matirne on cancer metabolism. Matrine inhibits autophagy by impairing the function of lysosomal protease, leading to a significant reduction in KRAS‐driven pancreatic cancer proliferation by suppressing autophagy‐mediated mitochondrial metabolic demands. Thus, matrine might be an effective candidate as a therapeutic agent for KRAS‐driven pancreatic cancer.