Regulatory RNase 1 (Regnase-1)

Regulatory RNase 1, commonly known as Regnase-1 and encoded by the ZC3H12A gene, is a pivotal endoribonuclease that serves as a master regulator of immune and inflammatory responses. It functions by binding to specific stem-loop structures in the 3' untranslated regions (UTRs) of target messenger RNAs (mRNAs), such as those for Interleukin-6 (IL-6) and Interleukin-12 (IL-12), and promoting their degradation. This post-transcriptional control is essential for preventing excessive inflammation and maintaining immune homeostasis. In oncology, Regulatory RNase 1 has emerged as a significant therapeutic target; its genetic deletion or pharmacological inhibition in T cells and CAR-T cells enhances their metabolic fitness, persistence, and antitumor activity by stabilizing key transcription factors like BATF. However, systemic inhibition of this target poses a risk of severe autoimmunity and hyperinflammation, as evidenced by the lethal inflammatory phenotypes observed in knockout models. Current drug development efforts, including small-molecule inhibitors, aim to harness its potential in cancer immunotherapy while managing these safety concerns.

Other names

ZC3H12AMCPIP-1Monocyte chemoattractant protein-induced protein 1MCPIP1Zinc finger CCCH-type containing 12A

Regnase-1 inhibitors prevent the degradation of target mRNAs by binding to the ribonuclease domain, thereby modulating the expression of pro-inflammatory or anti-inflammatory factors. In adoptive cell therapy, the deletion or inhibition of Regnase-1 stabilizes key mRNAs such as BATF and TCF-1, which enhances T-cell persistence, metabolic fitness, and antitumor activity.