Saussurea medusa Maxim extract suppresses triple‑negative breast cancer growth by disrupting mitochondrial lipid metabolism via the PPARα/CPT1A fatty acid oxidation axis

Triple‑negative breast cancer (TNBC) lacks effective targeted therapies and exhibits pronounced metabolic plasticity. Mitochondrial lipid metabolism and fatty acid oxidation (FAO) represent potential vulnerabilities. We investigated the antitumor activity and mechanism of Saussurea medusa Maxim extract (SMME) in TNBC models. SMME was profiled by HPLC–HRMS. Antitumor phenotypes, including viability, apoptosis, migration, and ultrastructural changes, were evaluated in TNBC cells. In vivo efficacy was assessed using an orthotopic 4T1 mouse model. Mechanism discovery relied on integrated proteomics and metabolomics. To validate target causality, we performed intracellular ATP quantification, representative active monomer evaluation, and pharmacological rescue assays. SMME and its representative active monomer inhibited cell viability across human and murine TNBC models. Furthermore, SMME impaired cell migration, induced apoptosis, and suppressed orthotopic tumor growth in vivo without obvious toxicity. Ultrastructural analysis revealed mitochondrial swelling and lipid droplet accumulation, which was accompanied by decreased intracellular ATP levels, suggesting impaired cellular bioenergetics. Integrated omics identified the PPARα/CPT1A-mediated fatty acid oxidation (FAO) axis as the primary metabolic target. Western blotting confirmed that SMME downregulated PPARα and CPT1A while activating intrinsic apoptosis. Subsequent pharmacological activation of PPARα successfully restored target protein expression and reversed SMME-induced cytotoxicity. SMME exerts significant antitumor effects against TNBC in vitro and in vivo. Multi-omics profiling and targeted validation suggest that the suppression of the PPARα/CPT1A-associated FAO program contributes to energy stress, lipid remodeling, and apoptosis, supporting mitochondrial lipid metabolism as a potential therapeutic target in TNBC.