Dihydrotanshinone I suppresses glycolysis and gastric cancer growth by targeting the nuclear FBXW11/LTN1/PKM2 axis.

BACKGROUND

Gastric cancer (GC) is a major global health problem, particularly in Asia. Dihydrotanshinone I (DHT), a naturally derived and commercially available compound isolated from Salvia miltiorrhiza, exhibits potential anti-GC activity through the modulation of cancer metabolism.

PURPOSE: This study aimed to investigate the anti-GC effects of DHT and elucidate the molecular mechanisms through which DHT regulates glycolysis.

STUDY

DESIGN

Integrated molecular profiling, functional experiments, and clinical sample analyses were employed to evaluate the pharmacological effects and mechanism of DHT in gastric cancer.

METHODS

The pharmacological targets and signaling pathways regulated by DHT were identified using RNA sequencing, chromatin immunoprecipitation sequencing, and immunoprecipitation-mass spectrometry. Functional validation was performed using in vitro assays and in vivo models. Clinical GC specimens were analyzed for associations between target gene expression, clinicopathological features, and patient prognosis.

RESULTS

DHT selectively inhibited GC cell proliferation at low concentrations while sparing normal gastric epithelial cells. Nuclear FBXW11 was identified as a direct target and was upregulated in GC tissues. This upregulation was correlated with advanced TNM stage and poor prognosis. The suppression of nuclear FBXW11 expression reduced glycolysis, invasion, and proliferation. Mechanistically, DHT promoted the LTN1-mediated ubiquitin-proteasome degradation of PKM2, thus suppressing glycolysis.

CONCLUSION

Dihydrotanshinone I suppresses GC progression via the FBXW11/LTN1/PKM2 axis, highlighting its potential as a metabolism-targeting phytochemical with low toxicity and translational relevance. Unlike previously reported DHT mechanisms involving oxidative stress, DNA damage, or immune modulation, our findings reveal a previously unrecognized nuclear ubiquitination-mediated metabolic regulatory axis in gastric cancer.