Novel biomimetic photosensitive nanoparticles delivering siZDHHC15 suppress YAP/CYR61 axis for combined photothermal-gene therapy against OSCC

ZDHHC15 regulates YAP localization and YAP/CYR61 signaling in OSCC. • PA supports OSCC migration through lipid metabolism-linked signaling. • R-LPA@siZDHHC15 enables targeted siRNA delivery and photothermal response. • The nanoplatform suppresses OSCC growth and lung colonization in models. This study aimed to elucidate the molecular mechanism by which ZDHHC15 promotes oral squamous cell carcinoma (OSCC) progression through regulation of the YAP/CYR61 signaling axis. Metabolomic and transcriptomic analyses revealed prominent lipid metabolic reprogramming in OSCC cells, with palmitic acid (PA) driving activation of the YAP transcriptional program and promoting cell migration and lung colonization. Functional experiments showed that ZDHHC15 enhanced YAP nuclear localization and transcriptional activity, leading to increased CYR61 expression and establishment of the ZDHHC15/YAP/CYR61 signaling axis. In addition, we developed a novel nanoplatform, R-LPA@siZDHHC15, which exhibited photothermal responsiveness and tumor-targeted delivery in vivo . When combined with photothermal therapy, this platform suppressed OSCC cell proliferation and tumor growth under the tested conditions. Collectively, these findings provide mechanistic insight into OSCC progression and support targeting the ZDHHC15/YAP/CYR61 axis as a potential therapeutic strategy, while further control and thermal-monitoring studies are needed to fully define the nanotherapeutic contribution. Schematic representation of the molecular mechanism by which R-LPA@siZDHHC15 modulates the YAP/CYR61 axis, thereby achieving combined photothermal and gene therapy to suppress OSCC progression. Download: Download high-res image (152KB) Download: Download full-size image