The ZFP36 Family as Post-Transcriptional Regulators in Physiology and Disease

The ZFP36 family proteins (TTP, ZFP36L1, and ZFP36L2) are RNA-binding proteins that function as key post-transcriptional regulators of gene expression. They bind AU-rich elements (AREs) in target mRNA 3'UTRs, recruit the CCR4-NOT deadenylation complex to trigger mRNA decay, and maintain homeostasis in immunity, barrier function, and stem cell fate. Rather than acting on single targets, all family members share a conserved mRNA destabilization mechanism, with outcomes determined by member-specific expression, kinase-mediated regulation, and cell-type-dependent target availability. Dysregulation of this network stabilizes mRNAs encoding pro-inflammatory cytokines, immune checkpoints, and oncogenes, driving pathogenesis of inflammation, autoimmunity, cancer, cardiovascular and neurodegenerative diseases. Individual family members exert context-dependent and sometimes opposing effects, so their net function depends on the specific cellular and disease context. Therapeutic strategies targeting ZFP36 activity, including phosphatase agonism and epigenetic modulation, have shown promising preclinical results, but clinical translation remains early. This review summarizes the molecular regulatory networks of the ZFP36 family and their physiological and pathological roles, emphasizing the mechanistic principles that unify family-member function and the contextual factors that diversify it, to provide a foundation for future therapeutic development.