## 4 Discussion  
An expanding number of studies have suggested that various herbs have an enormous yet unexploited potential for anticancer activity. They are appealing candidates for developing modern adjuvant therapeutics to overcome chemoresistance via \"multiple molecular mechanisms\" and \"multi-component and multi-target\" manifestations [41]. To date, many studies have shown that active compounds of distinct _Artemisia_ species induce apoptosis in cancer cells [42]. [PERSON] et al. demonstrated that an extract of _A. annua_ Linne (AAE) exerted apoptotic activities in in vitro and in vivo studies via modulation of phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathways [43]. However, we are the first group to demonstrate that the ASE can inhibit the cell viability of NSCLC cells. In agreement with previous studies, the ASE predominantly activated caspase-3 and its cleavage in the H23 cell line, and we propose that cell growth inhibition was correlated with caspase-dependent apoptotic cell death. Surprisingly, the results from Annexin V/7-AAD double-staining pointed out that another mode of cell death prevailed in A549 cells. Our study indicated that the ASE can simultaneously cause multiple forms of tumor cell death, whereby the NSCLC cells could be susceptible to distinct forms of cell death, either apoptosis or iron-dependent programmed ferroptosis. Artemisinin (ART) is a natural active compound isolated from the traditional Chinese plant _A. annua_ and was formerly used as an antimalarial drug. Recently, it was discovered that a semisynthetic derivative of this compound could induce ferroptosis in tumor cells, triggered by iron-dependent lipid peroxidation [44]. ART induces ferroptosis primarily by activating intracellular ROS production in cancer cells, depending on the ferritin level [45]. Several reports pointed out the importance of intracellular free iron concentrations in ferroptosis and proteins involved in iron uptake, storage, and processing that may regulate ferroptosis [46]. In our study, the ASE-induced ROS accumulation and lipid peroxidation prevailed in A549 cells, and these amendments were attenuated when cells were treated with DFO, an iron-chelator. Linking their findings to previous research, [PERSON] and colleagues discovered that ferroptosis inducers were more cell-line selective than other compounds (\(p<0.01\)), allowing the identification of biomarkers that may predict the sensitivity of cells to certain cell death inducers using cell line-selective filters [47]. That might be one prospective explanation relevant to our results that certain cell lines are preferentially sensitive to ASE-induced ferroptosis. Moreover, many of NRF2's downstream genes are involved in iron/heme, lipid metabolism, and apoptosis, making it a significant regulator of redox homeostasis [48]. [PERSON] et al. discovered that a root extract of _Beilschmiedia tsangii_ (BT extract) is a potential selective regulator of NRF2 signaling and can suppress NRF2 signaling in NRF2-hyperactivated Huh7 cells while activating it in HaCaT cells [49]. The findings from other studies also underscore how the balance of NRF2 protein levels in A549 and H23 cells impacts the overall response to cisplatin therapy, with immunofluorescence images of