Dihydroartemisinin targets GPX4 to induce autophagy-dependent ferroptosis and reduce radioresistance in triple-negative breast cancer

Breast Cancer is one of the most common malignancies and a leading cause of mortality among women worldwide. Triple-negative breast Cancer (TNBC) accounts for 15-20 % of all breast Cancer cases and is characterized by poor prognosis, high invasiveness, and a propensity for metastasis. Radiotherapy is a crucial component of multimodal therapy for TNBC, serving primarily as an Adjuvant modality following surgery or for local control in locally advanced disease. However, tumor tissues gradually adapt to radiation exposure, leading to the development of radioresistance-a phenomenon where Cancer cells survive and proliferate despite radiotherapy, significantly compromising treatment efficacy and patient outcomes. In recent years, numerous studies have reported that the herbal compound dihydroartemisinin (DHA) may serve as a radiosensitizer to enhance tumor sensitivity to radiation while reducing radiotoxicity in surrounding normal tissues. Nevertheless, the underlying mechanisms remain insufficient to meet clinical translation demands. Thus, identifying novel targets and alternative sensitization mechanisms is urgently needed. Here, we report that DHA overcomes acquired radioresistance by orchestrating a novel autophagy-dependent Ferroptosis pathway. We demonstrate that DHA directly binds to and promotes the ubiquitination-mediated degradation of GPX4, a key guardian against Ferroptosis. This degradation leads to intracellular Fe²⁺ accumulation and lethal lipid peroxidation. Crucially, we establish that Autophagy acts as an essential upstream mechanism enabling GPX4 degradation, thereby bridging DHA-induced stress to ferroptotic execution. Both Atg5 knockdown and pharmacological inhibition of Autophagy prevented DHA-induced GPX4 loss and the consequent radiosensitization. Collectively, our findings reveal a previously unrecognized mechanism in which DHA overcomes TNBC radioresistance by co-opting the Autophagy pathway to degrade GPX4 and unleash Ferroptosis, presenting a promising therapeutic paradigm targeting the autophagy-ferroptosis axis for refractory TNBC.

Autophagy-dependent ferroptosis; Dihydroartemisinin; GPX4; Radioresistance; Triple-negative breast cancer.