ANKIB1 is an E3 ubiquitin ligase containing ankyrin repeat and IBR domains that regulates innate immune signaling through K48- and K11-linked polyubiquitination of key signaling proteins. 1 ANKIB1 suppresses RLR-mediated antiviral responses by promoting K48-linked polyubiquitination and proteasomal degradation of MAVS, with ANKIB1 deficiency increasing type I interferon production and antiviral immunity. 2 ANKIB1 catalyzes K11-linked ubiquitination of TLR3 and cGAS-STING signalosome components, recruiting Optineurin to facilitate TBK1 and IRF3 activation; ANKIB1 deficiency impairs interferon induction while reducing interferonopathy. 3 ANKIB1 functions as an RBR-family E3 ligase partnering with UBE2L3 and UBE2D-family E2 enzymes, enabling structural and mechanistic analysis of E3 ligase functions. Beyond immune regulation, circular RNA derived from ANKIB1 (circ_ANKIB1) modulates osteosarcoma chemoresistance and cell growth through competing for microRNA-26b-5p and miR-19b, affecting EZH2 and STAT3 pathway signaling. 4 5 Additionally, ANKIB1 genetic variants associate with handedness and potentially with diabetic foot ulcer complications. 6 7 These findings establish ANKIB1 as a critical immunoregulator with dual capacity to activate and suppress innate immunity depending on substrate specificity, alongside roles in cancer biology and neurological traits.