Neohesperidin Dihydrochalcone Inhibits Ferroptosis Through System Xc− Modulation

Ferroptosis, a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides, is increasingly recognized as a critical pathogenic mechanism in various human diseases. Given the significant implication of ferroptosis in pathology, there is an urgent need to identify novel chemotypes with anti-ferroptotic activity. Recently, natural products have garnered attention as safe and effective sources for ferroptosis regulators. In this study, we identified Neohesperidin dihydrochalcone (NHDC), a flavonoid sweetener derived from citrus fruits, as a potent inhibitor of ferroptosis. We demonstrated that NHDC significantly restored cell viability in HT-1080 cells treated with Erastin, a System Xc− inhibitor. Mechanistically, NHDC treatment effectively mitigated the accumulation of lipid reactive oxygen species (ROS) and modulated the expression of ferroptosis-related proteins, including SLC3A2, SLC7A11, and PTGS2. Furthermore, NHDC exhibited a protective effect against ferroptosis induced by Sulfasalazine (SAS), another System Xc− inhibitor, by reverting SAS-induced lipid ROS levels. Interestingly, NHDC showed selectivity in its protective mechanism, distinguishing its activity from RSL3-induced ferroptosis pathways. Collectively, our findings demonstrate that NHDC acts as an effective anti-ferroptotic agent by targeting System Xc− inhibition. This study provides valuable insights into the therapeutic potential of NHDC as a natural candidate for the treatment of ferroptosis-related diseases. Citation Format: Bomi Han, Yi-Xi Gong, Seonghye Son, Eui Man Jeong, . Neohesperidin dihydrochalcone: A novel natural inhibitor of ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3667.