The authors state that artesunate promotes ferritin degradation and sensitizes cells to ferroptosis, likely by sequestering iron in lysosomes, and that this action is “independent of autophagy and NCOA4” [Page 11]. This claim is highly significant as NCOA4-mediated ferritinophagy is the principal and well-established pathway for ferritin degradation. To assert a novel, parallel mechanism requires exceptionally robust and direct evidence. The provided references [176, 177] do not conclusively demonstrate this autophagy/NCOA4-independent pathway. Without definitive genetic knockout experiments (e.g., in ATG5/7/NCOA4 null cells) showing that artesunate-induced ferritin degradation and ferroptosis-sensitization remain fully intact, this claim is premature and represents a potential overinterpretation of data. This could misdirect future research by suggesting a major alternative mechanism that may not be fully validated.
