Fig. 4.

Hypoxia and ferroptosis.

Hypoxia is a hallmark of the tumor microenvironment and thereby a relevant factor when considering ferroptosis for tumor therapy. Major regulators of hypoxia are the HIF transcription factors. HIF-1 increases transcription of SLC7A11 and HO-1, which both protect from ferroptosis [42,43]. In contrast, HIF-2 was shown to increase the expression of PLIN2 and HILPDA, which elevate lipid accumulation, oxidative stress, and finally enhance ferroptosis [44]. Besides HIF, hypoxia is known to increase the activity of Nrf2, which is a major regulator of the anti-oxidative system. Increased Nrf2 activity under hypoxia facilitates HO-1 expression and thus, protects from ferroptosis [45,46]. The HIF- and Nrf2-pathways are known to interact with each other and thus, facilitate target gene expression [47]. Besides activation of these major regulatory mechanisms, expression of proteins such as SCD1 increases under hypoxia. This increase might compensate for the lack of O₂, which is a substrate of SCD1. Nevertheless, SCD1 was shown to protect hypoxic cells from ferroptosis by generating MUFAs [48]. In addition, SCD1 has a ferroxidase activity, which potentially attenuates ferroptosis by limiting intracellular Fe²⁺. Another mechanism which reduces Fe²⁺ and, thus, the LIP is the storage of iron by ferritins. NCOA4-mediated degradation of ferritins and the release of iron into the LIP is facilitated by ferritinophagy. This process is inhibited by decreased NCOA4 expression under hypoxia, which increases iron storage and in turn protects cells from ferroptosis [12,49]. Furthermore, inhibition of CA9 blocked ferritin-mediated iron storage and increased transferrin receptor abundance, which sensitized cells towards ferroptosis. An induction of CA9 under hypoxia reduces oxidative stress and thus ferroptosis [50].