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Population genetic structure, historical biogeography and historical demography of the alpine toad Scutiger ningshanensis were studied using the combined data mtDNA cytochrome b (cyt b) and the mtDNA cytochrome c oxidase subunit I (COI) as the molecular markers. This species has high genetic variation. There was a significant genetic differentiation among most populations. Three lineages were detected. The phylogenetic relationship analyses and the SAMOVA (spatial analysis of molecular variance) results showed significant phylogeographic structure. 82.15% genetic variation occurred among populations whereas differentiation within populations only contributed 17.85% to the total. Mantel test results showed a significant correlation between the pairwise calculated genetic distance and pairwise calculated geographical distance of the populations (regression coefficient  = 0.001286, correlation coefficient  = 0.77051, p (rrand≥robs)  = 0.0185<0.05), indicating the existence of isolation-by-distance pattern of genetic divergence for cyt b + COI sequence, which suggests that the distribution of genetic variation is due to geographical separation rather than natural selection. The population expansion or contraction and genetic differentiation between populations or lineages could be explained by topography and the repetitive uplifts of the Tsinling Mountains and the climatic cycles during the late Pliocene and Pleistocene. S. ningshanensis experienced a rapid population expansion about 40,000 years before present. The current decline in population size was probably caused by anthropogenic disturbance. Current populations of S. ningshanensis are from different refugia though the location of these refugia could not be determined in our study. Topography, climatic changes and repetitive population expansion/contraction together led to the high level of genetic variation in S. ningshanensis. A total of three management units (MUs) was determined, which must be considered when conservation policy is made in the future.

Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.