Magnolia officinalis Lignans induce apoptosis and epigenetic reprogramming via the miR-148a-3p/DNMT-1/UTF-1 axis in pancreatic cancer cells.

Abstract

<p>Magnolia officinalis Rehder et Wilson (MRW) is a traditional herbal medicine with well-documented anti-inflammatory and antioxidative properties, yet its molecular basis in cancer therapy remains incompletely defined. This study aimed to elucidate the multi-target anticancer potential of MRW against pancreatic cancer through integrated in vitro and in silico analyses. LC-MS/MS profiling identified honokiol and magnolol as the major bioactive constituents, confirmed by retention time and UV spectra. MRW treatment suppressed cell viability and induced apoptosis in PANC-1 and MIA PaCa-2 cells by promoting reactive oxygen species (ROS) generation, mitochondrial membrane potential (∆Ψm) depolarization, and caspase activation, while sparing normal epithelial cells. Mechanistically, MRW inhibited DNA methyltransferase 1 (DNMT-1) and JAK2/STAT3 signaling while restoring undifferentiated embryonic cell transcription factor 1 (UTF-1) and miR-148a-3p expression, thereby reversing the epigenetic silencing and ROS overproduction characteristic of pancreatic cancer cells. Molecular docking further demonstrated strong binding affinities of honokiol, magnolol, and magnolin toward DNMT-1, UTF-1, STAT3, JAK2, IL-6, and Survivin, forming stable hydrogen-bond and π-π stacking interactions within catalytic pockets. These interactions suggest that MRW constituents' function as non-nucleoside DNMT-1 inhibitors and ROS-immune modulators that disrupt oncogenic feedback loops and re-activate apoptotic pathways. Collectively, these findings identify MRW as a multi-target phytomedicine integrating ROS-mediated oxidative stress, epigenetic remodeling, and immune-apoptotic signaling, supporting its translational potential as a low-toxicity adjunct strategy to conventional pancreatic cancer therapies.</p>