Jianpi Huayu decoction exerts antitumor effects in pancreatic cancer via SCD1-mediated lipid metabolism remodeling/ferroptosis axis

Background: Pancreatic Cancer (PC) is a highly aggressive malignancy associated with a poor prognosis. Its clinical management is particularly challenging due to factors such as tumor metastasis and drug resistance, emphasizing the need for alternative therapeutic strategies. Traditional Chinese Medicine (TCM) has attracted growing interest as a potential Cancer treatment owing to its distinctive advantages, including multi-target effects and a favorable safety profile. Jianpi Huayu decoction (JPHYD), a TCM formula developed by our team as an Adjuvant therapy for hepatopancreatic malignancies, has demonstrated anti-tumor activity in preliminary studies. However, the precise mechanisms of action against PC remain unclear.

Objective: To investigate the anti-tumor efficacy of JPHYD against PC and elucidate the underlying mechanisms.

Methods: The antitumor effects of JPHYD-containing serum (2.5 %, 5 %, and 10 %) on PANC-1 and SW1990 were evaluated using a series of in vitro assays, including CCK-8 cell viability, colony formation, EdU proliferation, wound healing, transwell invasion, Apoptosis, and Western blot analyses. To investigate the underlying Anticancer mechanisms, transcriptomics, untargeted metabolomics, overexpression plasmid transfection, RT-qPCR, immunohistochemistry, BODIPY staining, triglyceride (TG) quantification, and Apoptosis and Ferroptosis assays were conducted. Ferroptosis was assessed via Live/Dead staining, intracellular Fe²⁺, malondialdehyde (MDA), and glutathione (GSH) levels, C11-BODIPY staining, transmission electron microscopy, and Western blotting. In vivo, both subcutaneous and orthotopic xenograft tumor models were established in BALB/C nude mice to evaluate the antitumor efficacy of JPHYD. Based on experimental design requirements, different doses of JPHYD were administered via intragastric gavage (low dose: 3.844 g/kg/d; medium dose: 7.689 g/kg/d; high dose: 15.378 g/kg/d). To uncover active compounds, we employed a multi-level strategy that integrated UPLCHRMS analysis, in silico modeling (docking and dynamics simulations), and CETSA-based validation.

Results: Consistent results from in vitro and in vivo models demonstrated that JPHYD effectively impaired pancreatic Cancer progression without notable toxicity. Transcriptomic and untargeted metabolomic analyses indicated that JPHYD's anti-tumor effects may occur through stearoyl-CoA desaturase 1 (SCD1) -mediated lipid metabolic remodeling. Specifically, JPHYD suppresses SCD1 expression, reducing intracellular lipid accumulation and disrupting lipid homeostasis. Concurrently, this disruption enhances JPHYD-induced Ferroptosis in PC cells, evidenced by accelerated GSH depletion, MDA accumulation, elevated intracellular Fe²⁺ levels, antioxidant system imbalance, and increased lipid peroxidation. The Ferroptosis inhibitor (Ferrostatin-1, Fer-1) significantly reversed these effects. Mechanistic studies further revealed that overexpression of SCD1 restores lipid homeostasis in PC cells, substantially attenuating JPHYD-induced Ferroptosis. Notably, Comprehensive screening identified dihydrotanshinone I (DHT) as a potential key active component of JPHYD responsible for SCD1 regulation. Molecular docking, molecular dynamics simulations, and CETSA experiments confirmed strong binding affinity between DHT and SCD1. In vitro, DHT treatment alone reduced PC cell viability, SCD1 protein expression, and intracellular lipid accumulation while significantly increasing lipid peroxidation and inducing Ferroptosis.

Conclusions: Our work demonstrates that JPHYD exerts potent antitumor activity in PC by modulating SCD1-mediated lipid remodeling and inducing Ferroptosis. We further identified DHT, a natural bioactive compound, as a potential SCD1 inhibitor. These results highlight the therapeutic promise of JPHYD and DHT and open new perspectives for developing effective strategies against PC.

Ferroptosis; JianPi Huayu decoction; Lipid metabolism; Pancreatic cancer; SCD1.