Hypoxia-mediated regulation of mRNA metabolism: from transcription to stability.

BACKGROUND: Hypoxia plays a critical role in both physiological and pathological processes. Cells adapt to hypoxia through the extensive reprogramming of gene expression. While the transcriptional regulations of hypoxia-inducible factors (HIFs) are well-studied, recent advances have emphasized the importance of post-transcriptional regulation, including mRNA translation, modification, stability, and degradation. Summarizing the regulation of mRNA homeostasis under hypoxia will improve our understanding of how hypoxia contributes to diseases such as cancer and ischemic injury. MAIN BODY: This review systematically summarizes the regulation of mRNA metabolism by hypoxia across multiple levels. First, hypoxia remodels mRNA transcription initiation and elongation. HIF-1 plays a critical role in this process by recruiting RNA polymerase II and releasing promoter-proximal pausing. Second, hypoxia suppresses global protein synthesis by phosphorylating eIF2α and inhibiting mTOR, while selectively upregulating key mRNAs (e.g., VEGFA) via internal ribosome entry sites (IRES). Third, hypoxia influences mRNA modifications, including m6A, m5C, and ac4C, thereby modulating mRNA stability and translation. Lastly, hypoxia influences mRNA stability and degradation through poly(A) tail dynamics and AU-rich elements. CONCLUSION: Hypoxia orchestrates mRNA metabolism through interconnected transcriptional and post-transcriptional mechanisms, enabling cells to adapt to oxygen deprivation. RNA-binding proteins play a role throughout the entire lifespan of mRNA and could serve as potential therapeutic targets for the treatment of hypoxia-related diseases.