Esophageal　squamous　cell　carcinoma　(ESCC)　is　a　severe　malignancy　with　high　incidence　and　mortality　rate　in　China,　while　the　application　of　standard　chemotherapeutic　drugs　for　ESCC　meets　the　barriers　of　high　toxicity　and　multiple　drug　resistance　(MDR).　In　recent　years,　the　anticancer　effects　of　artesunate　(ART),　a　Chinese　medicine　monomer　have　gained　extensive　attentions　due　to　its　characteristics　of　low　toxicity,　high　potency,　and　reversal　of　MDR.　In　this　study,　we　develop　the　artesunate-loaded　solid　lipid　nanoparticles　(SLNART)　to　overcome　the　poor　water　solubility　and　bioavailability　of　ART,　further　improving　the　efficiency　of　ART　on　ESCC　treatment.　Especially　mentioned,　SLNART　is　shown　to　present　marked　inhibitory　effects　on　ESCC　development　based　on　the　induction　of　ferroptosis　by　two　pathways　included　upregulating　TFR　to　increase　Fe2+　ions　and　inhibiting　the　AKT/mTOR　signaling　to　downregulate　GPX4.　Collectively,　this　study　is　the　first　to　pave　a　promising　approach　for　ESCC　therapy　based　on　a　strategy　of　developing　SLNART　to　induce　ferroptosis　by　mediating　Fe2+　ions　and　AKT/　mTOR　signaling.