Abstract 2822: AdipoRon suppresses breast cancer growth through autophagy-mediated ferroptosis

Abstract Excess adipose tissue and the release of large amounts of adipokines are recognized as contributing factors in the development of various cancer types. Adiponectin, distinct from other adipokines, is negatively correlated with cancer progression. Low serum levels of adiponectin have been correlated with dysregulated cellular metabolism, including lipid and glucose metabolism, as well as increased cancer cell aggressiveness. Additionally, elevated adiponectin has been characterized as an anti-tumor factor with potential as a therapeutic target. However, due to its large size and protein instability, the development of adiponectin as a drug has been challenging. Recently, an oral adiponectin receptor agonist, AdipoRon, has been identified and is currently under investigation as a potential cancer treatment. Given that breast cancer is known to be highly influenced by surrounding adipose tissue, we utilized the breast cancer cell models to further evaluate the effects of AdipoRon on cancer progression. Cell viability of various breast cancer cell lines across subtypes was reduced by AdipoRon supplementation, and autophagy was induced in a dose-dependent manner, with significant LC3 lipidation and autophagosome formation. In addition, AdipoRon led to the accumulation of free radicals in mitochondria, accompanied by morphological changes and functional disruption, which in turn caused mitophagy. Lipid metabolism of cancer cells was also impaired by AdipoRon, with a decline in fatty acid storage capacity. The increased free fatty acids were further oxidized, resulting in lipid peroxide accumulation, a hallmark of ferroptosis. Other characteristics of ferroptosis, including ferritinophagy, iron accumulation and a decrease in glutathione peroxidase 4 level, were also observed in AdipoRon-treated cells. Moreover, AdipoRon-induced cell death could be rescued by a ferroptosis inhibitor, ferrostatin, suggesting that ferroptosis was induced by AdipoRon in breast cancer cells. Mechanistically, we identified BECN1, the key regulator of autophagy, as a critical factor in AdipoRon-associated ferroptosis. Knockdown of BECN1 significantly rescued the ferroptotic cell death and related characteristics in breast cancer cells. Collectively, our data demonstrate that AdipoRon induced cell death in breast cancer cells by disrupting cellular metabolic capacity and triggering ferroptosis, a mechanism that has not been previously reported. These findings suggested the therapeutic potential of AdipoRon in inhibiting breast cancer progression. Citation Format: Yong-Han Su, Yi-Zhen Wu, Hsin-Yi Yang, Tzu-Yi Chia, Jou-Fang Hsu, Ching-Ying Kuo. AdipoRon suppresses breast cancer growth through autophagy-mediated ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2822.