BACKGROUND: Peripheral T cell lymphoma (PTCL) is characterized by high heterogeneity, strong aggressiveness, and extremely poor prognosis. Ferroptosis, a novel form of programmed cell death, has been involved in tumor development and targeting ferroptosis holds great potential for tumor therapy. METHODS: Lentiviral transfection was performed to regulate gene expression, followed by Tandem mass tag (TMT)-mass spectrometry and RNA-sequencing. Tumor xenograft models were established for in vivo experiments. RESULTS: High expression of prostaglandin D2 synthase (PTGDS) was closely associated with poor prognosis of PTCL patients. PTGDS knockdown and AT56 treatment significantly inhibited the progression of PTCL through regulating cell viability, proliferation, apoptosis, cell cycle and invasion in vitro and in vivo. We further revealed that targeting PTGDS promoted ferroptosis process and enhanced the sensitivity of PTCL cells to ferroptosis inducers Sorafenib in vitro and in vivo. Mechanically, PTGDS interacted with heme-degrading enzymes HMOX1, and targeting PTGDS increased the level of iron and induced ferroptosis in PTCL through promoting HMOX1-mediated heme catabolism and ferritin autophagy process. Through the construction of H25A mutation, the specific gene site of HMOX1 corresponding to its role was identified. CONCLUSIONS: Taken together, our findings firstly identified that targeting PTGDS promotes the ferroptosis in PTCL through regulating HMOX1-mediated iron metabolism, and highlighted novel therapeutic strategies to improve the efficacy of ferroptosis-targeted therapy in PTCL patients.