Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with high incidence, low survival rates, and poor prognosis. Current treatments are unsatisfactory, highlighting the need for novel agents. Celastrol (Cela), from Tripterygium wilfordii, shows anti-ESCC potential, but its direct inhibitory mechanisms remain unclear.
Objective: This study explores Cela's effects on ESCC cell proliferation, migration, and invasion, utilises metabolomics and proteomics to identify its anti-ESCC mechanisms, and validates these findings via molecular techniques and ferroptosis inhibitor tests.
Methods: ESCC lines EC109 and KYSE520 were treated with different Cela concentrations. Proliferation (CCK-8), migration (wound healing), and invasion (Transwell) were assessed. Metabolomics, proteomics, Western blot/RT-qPCR, and Fe²⁷/MDA/GSH measurements were conducted. Rescue experiments used 1 µM Ferrostatin-1 [1].
Results: Cela inhibited ESCC functions dose-dependently, inducing ferroptotic phenotypes (elevated Fe²⁷/MDA, reduced GSH). Multi-omics analysis revealed ferroptosis pathway enrichment; the specific ferroptosis inhibitor Fer-1 reversed these Cela-induced ferroptotic phenotypes and restored ESCC functions, confirming ferroptosis as the key mediating pathway.
Discussion: Cela's anti-tumor potential is supported by existing patents [2-4]; this study adds a novel mechanism: ferroptosis-mediated inhibition of ESCC invasion and metastasis.
Conclusion: Cela inhibits ESCC invasion and metastasis via TFRC/HMOX1-mediated ferroptosis, with multi-omics providing systematic mechanistic insights. This study uncovers a novel ferroptosis-centred anti-ESCC mechanism, supporting Cela's therapeutic potential.
Keywords: Celastrol; esophageal squamous carcinoma; ferroptosis; metabolomics; multi-omics; proteomics.
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