Honokiol modulates invasion and autophagy in pancreatic cancer via the miR-101/QKI axis in cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) promote the pathological process of pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignant tumor. Autophagy plays a dual role in cancer, and in the context of PDAC, increased autophagy significantly promotes PDAC cell survival and metastasis. We aimed to investigate whether honokiol, a naturally occurring compound with anti-cancer properties, regulated the miR-101 /QKI axis to suppress CAF-mediated autophagy, proliferation, and invasion in PDAC. CAFs isolated from PDAC specimens were treated with honokiol to evaluate its effects on the tumor microenvironment. Conditioned medium from honokiol-treated CAF was used to incubate with PDAC cells, and their malignant phenotypes (proliferation, invasion, autophagy) were assessed through a series of in vitro and in vivo functional assays. Molecular analyses elucidated honokiol/miR-101/QKI axis driving PDAC pathogenesis. Honokiol therapeutic validation conducted using a mouse xenograft model. MiR-101 expression was significantly downregulated in CAFs (∼2.8-fold), whereas QKI and α-SMA were upregulated (∼2.8-fold and ∼3.2-fold, respectively). Honokiol treatment (50 μM) enhanced miR-101 expression (∼2.5-fold), reduced QKI and α-SMA level (∼60 % and ∼55 % reduction, respectively) in CAFs. Conditioned media from honokiol-treated CAFs substantially suppressed PDAC cell autophagy, proliferation, migration, and invasion. Mechanistically, honokiol attenuated malignant PDAC cell phenotypes by inducing miR-101 expression in CAFs. QKI was identified as a miR-101 target in CAFs. MiR-101 overexpression in CAFs inhibited PDAC cell malignant behavior through QKI silencing. In mouse xenograft models, honokiol suppressed tumorigenesis by modulating miR-101 /QKI axis. Honokiol inhibits CAF-induced autophagy, proliferation, migration, and invasion in PDAC by regulating the miR-101/QKI axis, thereby modifying cancer cell behavior. This reveals the potential of honokiol as a promising therapeutic agent to remodel the tumor microenvironment and suppress pancreatic cancer progression.