Ferroptosis plays a dual role (promoting and suppressing cancer) in tumorigenesis and therapy resistance, and elucidating its regulatory mechanisms while exploring its therapeutic potential holds significant clinical value. The Piezo1 channel and the Nrf2/HO-1 pathway provide new perspectives for ferroptosis regulation. As a mechanosensitive ion channel, Piezo1 dynamically regulates iron metabolism through calcium signaling, exhibiting biomechanical microenvironment-dependent effects. The Nrf2/HO-1 pathway, on the other hand, confers ferroptosis resistance in tumor cells by regulating antioxidant enzyme expression. Their interaction reveals a complex regulatory network of ferroptosis and offers novel molecular targets for cancer treatment. In-depth research on ferroptosis mechanisms has advanced related therapeutic strategies, and traditional Chinese medicine (TCM) has demonstrated unique advantages in modulating ferroptosis pathways. This review will summarize the regulatory mechanisms of ferroptosis, the roles of the Piezo1 channel and Nrf2/HO-1 pathway, and discuss combined targeting strategies as well as the potential application of TCM-based interventions.