Mitochondrial targeted metformin stimulates ER stress-mediated apoptosis in human and mouse pancreas tumor cells

Pancreas cancer is one of the most aggressive human malignancies. Accumulating evidence has indicated metabolic reprogramming as a necessity for pancreas cancer growth, invasion, and chemotherapeutic resistance. In this study, we investigated the antitumor mechanisms of mitochondria-targeted Metformin, Mito-Met10, in human and mouse pancreas cancer cells and preclinical models. MMe treatment in vitro induced extensive cytoplasmic vacuolization, mitochondrial swelling, and significantly reduced mitochondrial membrane potential. RNA sequencing, qPCR, and immunoblot analysis of MMe-treated cells revealed upregulation of ER stress-associated genes and increased unfolded protein response-related proteins, including XBP1, peIF2α, and ATF4. Consistent with these findings, MMe treatment inhibited cell proliferation and induced caspase-3/7-mediated apoptosis. Furthermore, in vivo studies demonstrated that MMe localized within pancreas tumors and suppressed tumor growth fourfold relative to controls. These findings highlight MMe as a potential metabolic inhibitor that disrupts mitochondrial bioenergetics, induces ER stress, and promotes apoptosis in pancreatic cancer cells.