Fig. 6

A working model for YTHDF1. As proposed in this model, under normoxia conditions for NSCLC progression, YTHDF1 amplification or high expression mainly promotes the translational efficiency of targeted m⁶A-modified transcripts, such as cell cycle regulators including CDK2, CDK4, cyclin D1, etc., in cancerous cells, which causes uncontrolled cancerous cell proliferation. On the other hand, when YTHDF1 low expression NSCLC patients encounter chemotherapy stress condition, especially cisplatin treatment-induced reactive oxygen species (ROS) accumulation, decreased Keap1 translational efficiency leads to upregulation of Nrf2 and its downstream ARE responding factor antioxidant AKR1C1, which in turn renders cancerous cells resistance to cisplatin treatment, and eventually results in a worse clinical outcome. In contrast to YTHDF1 high expression in NSCLC cancerous tissues, YTHDF1 is decreased in highland cattle compared to that in lowland cattle. The Keap1-Nrf2-AKR1C1 axis is the same mediator for YTHDF1 low expression dependent hypoxia adaptation. Thus, the balance of YTHDF1 expression and its targeted m⁶A-modified mRNAs or interacting proteins between normoxia and hypoxia/cisplatin treatment (stressful) conditions is important both for non-pathological homeostasis and various human cancers, and it will be necessary to characterize these molecular events in the future