Ultrasound-Enhanced Delivery of Salvianolic Acid F Targets CXCL5 to Suppress Lung Cancer Progression: Insights from <i>In Vitro</i> PC9 and H1299 Models

<b><i>Background:</i></b> Lung cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for more effective and targeted therapeutic strategies. Traditional Chinese Medicine (TCM), known for its favorable safety profile and broad pharmacological effects, offers promising candidates for cancer treatment. Salvianolic acid F (SAF), a key bioactive compound derived from <i>Salvia miltiorrhiza</i>, has demonstrated antitumor potential, but its role and underlying mechanisms in lung cancer remain inadequately characterized. <b><i>Objective:</i></b> This study investigated the anticancer efficacy of SAF in lung cancer and determines whether ultrasound can enhance its therapeutic effects, with a particular focus on the CXCL5/Wnt/β-catenin signaling axis. <b><i>Methods:</i></b> Human non-small cell lung cancer cell lines H1299 and PC9 were treated with SAF alone or in combination with ultrasound. Cell proliferation, migration, and invasion were assessed using cell counting kit-8, scratch wound healing, and transwell assays, respectively. Gene expression changes were analyzed using RNA sequencing and validated by quantitative real-time polymerase chain reaction and Western blotting. Functional involvement of CXCL5 was further confirmed through small interfering RNA-mediated gene silencing. <b><i>Results:</i></b> SAF significantly inhibited proliferation, motility, and invasiveness of both H1299 and PC9 cells. These effects were markedly enhanced when SAF was delivered in conjunction with ultrasound exposure. Transcriptomic analysis revealed downregulation of CXCL5 and suppression of downstream Wnt/β-catenin signaling mediators, including Wnt5α and β-catenin. CXCL5 knockdown mimicked the inhibitory effects of SAF and synergized with SAF treatment, confirming the involvement of the CXCL5/Wnt/β-catenin axis in the observed antitumor response. <b><i>Conclusions:</i></b> Ultrasound-enhanced delivery of SAF significantly impairs lung cancer cell proliferation and metastasis by targeting the CXCL5/Wnt/β-catenin pathway. This combinatorial approach represents a novel and promising biotherapeutic strategy for lung cancer that integrates TCM-derived compounds with noninvasive delivery technologies.