A Novel Compound 3a-M1, from Metabolites of Sinomenine Derivative 3a, Exerts Potent Anti-Aplastic Anemia Activity via IP3R/ORAI-Mediated CTL Ferroptosis

Aplastic anemia (AA) is a refractory hematological disease with limited therapeutic effectiveness and serious treatment-related side effects. Cytotoxic T lymphocytes (CTLs) play a key role in AA pathogenesis. In our previous study, sinomenine derivative 3a was obtained, which demonstrated potential anti-AA activity by targeting CTLs with low toxicity. In this study, a novel metabolite, 3a-M1, was identified with optimized bioavailability from 3a metabolism, which exhibited a more notable effect in alleviating anemia symptoms, suppressing bone marrow CTLs activation, and improving hematopoietic function in immune-mediated bone marrow failure mouse models. In vitro experiments demonstrated that 3a-M1 directly inhibited CTLs activation and their killing function; the underlying mechanism was at least in part mediated by the selective ferroptosis of overactivated CTLs via the IP3R/ORAI pathway. These findings suggest that 3a-M1 represents a novel potential therapeutic agent for AA treatment and ferroptosis may serve as a promising target on CTLs for AA therapy.