Recently, Fenton reaction-mediated ferroptosis has attracted great attention in cancer treatment while the metabolism loss of iron and the limited endogenous HO level imped its clinical application. Here, a new ferroptosis inducer (Fe@cLANAs) constructed only by Fe(II) and (R)-(+)-lipoic acid (LA) was developed for tumor ablation. After entering the tumor cells, the Fe@cLANAs dissociated into disdihydrolipoic acid (DHLA) and released iron, which would regenerate each other to continuously provide iron and HO to enhance ferroptosis. The Fe@cLANAs demonstrated the IC below 10 μM against various tumor cells, an anti-tumor effect comparable to many chemotherapy drugs. In vivo antitumor evaluation based on the tumor cell-derived xenograft model showed a tumor inhibitory rate (TIR) of 97.4% at the iron usage of 1.53 mg/kg, the lowest iron usage reported so far in ferrotherapy using iron as the main agent to treat tumors. Notably, the good anti-tumor effect of Fe@cLANAs was further achieved in the glioma patient-derived xenograft (PDX) model. This strategy utilizing the reciprocal circulation of metal iron and LA to delay the metabolism loss of iron and increase the HO level in the tumor cells holds a great potential for ferroptosis-mediated cancer treatment. STATEMENT OF SIGNIFICANCE: The metabolism loss of iron and the limited endogenous HO level are key factors to impede the clinical application of ferroptosis-mediated cancer treatment. Herein, a new ferroptosis inducer constructed only by lipoic acid and iron is developed to delay the metabolism loss of iron and increase the level of endogenous HO by causing a cyclic regeneration of Fe(II)/Fe(III) and LA/DHLA in the tumor cells. According to the previous reports, at least 75 mg/kg of iron dosage was needed to achieve effective antitumor efficacy, here, the use of only 1.53 mg/kg iron in Fe@cLANAs achieved the TIR of 97.4% and 62.8% in the U251 CDX and glioma PDX models, showing the good prospect of Fe@cLANAs in clinic.