RC3H1 (Roquin-1) is a multifunctional post-transcriptional regulator that maintains immune homeostasis through RNA binding and ubiquitin ligase activities. The protein recognizes and binds to conserved stem-loop motifs called constitutive decay elements (CDEs) in target mRNAs, including ICOS, TNF, and TNFRSF4, promoting their deadenylation and degradation 1. RC3H1 functions as an E3 ubiquitin ligase, producing polyubiquitin chains when paired with various E2 enzymes, with strongest activity observed with UBE2N complexes 2. In T follicular helper cells, RC3H1 prevents spontaneous differentiation and autoimmunity by repressing ICOS and TNFRSF4 expression 3. The protein also regulates TNF expression in macrophages, with its activity modulated by interactions with other proteins like MNSFβ, which can promote RC3H1 localization to stress granules and reduce its mRNA-degrading function 45. Loss of RC3H1 function leads to autoimmune phenotypes similar to systemic lupus erythematosus, characterized by excessive T follicular helper cell activation and germinal center formation 1. Additionally, RC3H1 shows promise as a therapeutic target, as its inhibition enhances CAR T cell persistence and promotes ferroptosis in cancer cells through GPX4 regulation 62.