Endoribonuclease ZC3H12A (ZC3H12A)

Endoribonuclease ZC3H12A, widely known as Regnase-1 or MCPIP1, is a pivotal post-transcriptional regulator that maintains immune homeostasis by controlling the stability of inflammatory mRNAs [1, 2, 9]. It functions primarily as an endoribonuclease that recognizes and cleaves specific transcripts, such as those encoding IL-6 and IL-12b, by binding to conserved stem-loop structures in their 3' untranslated regions [2, 8, 11]. Beyond its RNase activity, ZC3H12A possesses deubiquitinating enzyme activity, allowing it to negatively regulate the NF-κB and JNK signaling pathways by targeting TRAF proteins [1, 3, 14]. In the context of disease, ZC3H12A acts as a vital brake on inflammation; its deficiency leads to severe systemic autoimmune and inflammatory syndromes [2, 12, 21]. In oncology, it exhibits a dual role, often acting as a tumor suppressor by inhibiting angiogenesis and promoting apoptosis, though its genetic knockout in CAR-T cells and tumor-infiltrating lymphocytes (TILs) has emerged as a potent strategy to enhance T-cell fitness and anti-tumor activity [1, 4, 20, 25]. While direct small-molecule inhibitors are currently in preclinical development, the target is being actively validated in clinical trials through gene-edited cellular therapies such as KSQ-004EX and CAR19TIF [17, 18, 22].

Other names

Regnase-1 [1, 2]MCPIP1 [1, 2]Monocyte chemotactic protein-induced protein 1 [9]Zinc finger CCCH domain-containing protein 12A [6, 9]MCPIP-1 [6]Reg1 [9]

ZC3H12A acts as an endoribonuclease that degrades pro-inflammatory mRNAs (e.g., IL-6, IL-12b) and a deubiquitinase that inhibits NF-κB and JNK signaling [1, 2, 9]. In cancer immunotherapy, its genetic inactivation (knockout) in T cells or TILs is used to enhance T-cell persistence, fitness, and anti-tumor efficacy by preventing the degradation of effector-promoting transcripts [18, 20, 25].