ADAR (Adenosine Deaminase RNA Specific)

The two codes of A-to-I and C-to-U RNA editing harbor common potential for single base conversion with varied expression of responsible enzymes across many physiological and pathological conditions. Here we provide a comprehensive and parallel overview on ADAR-mediated A-to-I and APOBEC-mediated C-to-U editing, with emphasis on their molecular mechanisms, physiological roles and pathological dysregulation in human health and disease.

Notably, combining the EBNA1-targeting PROTAC degrader EP-1215 with anti-PD-1 effectively restored IFN signaling, enhanced T-cell infiltration, and suppressed EBNA1+ tumors in humanized mice. This viral exploitation of RNA editing suggests that targeting EBNA1 could be a strategy to convert "cold" tumors into "hot" targets amenable to ICB therapy.

ADARB1 exerts its anti-tumor effects primarily through the HMGB1/PFKFB3 pathway. Collectively, these findings identify ADARB1 as a novel tumor suppressor in cervical cancer and a promising therapeutic target for clinical intervention.

We demonstrate that vaccines utilizing TOE mRNA encoding a tumor neoantigen (for normal translation) and an IL-12 adjuvant (with delayed translation) elicit significantly enhanced antitumor immune responses. TOE mRNA technology represents a promising platform for advancing next-generation mRNA vaccines with improved efficacy.

Our study identifies a novel pathway by which 8-Cl-Ado promotes ferroptosis through the ADAR1/miR-101-3p/SLC7A11 axis to suppress breast cancer progression. These findings highlight the therapeutic potential of 8-Cl-Ado as a ferroptosis-inducing agent by targeting ADAR1.

The DNA methylase inhibitor reactivated endogenous retroviruses, leading to the formation of retrovirus dsRNAs and the emergence of a new ADAR1 dependency. Our study establishes the potential of ADAR1i-124 as a future cancer therapeutic.

Mechanistically, ADAR1 deficiency in NK cells is accompanied by CD38 expression decline via affecting its mRNA stability, resulting in increased cell mobility, proliferation, and tumor killing capacity. Our findings validate ADAR1 as an emerging therapeutic target for enhanced NK cell immunotherapy.

ADAR1-imposed RNA editome suppresses HSC-intrinsic innate immunity and promotes collagen production, leading to aggravated HSC activation and liver fibrosis. Targeting ADAR1 with its pharmacological inhibitor or HSC-selective RNAi shows great promise in treating liver fibrosis.

Hence, surgical oncology researchers must explore RNA editing in-depth. It is worth noting that limited antitumor activity was observed in solid tumors in preclinical studies due to insufficient delivery of editing tools, indicating realistic translation expectation is needed.

These include degraders targeting resistant EGFR, antibodies depleting CD7+ pathogenic lymphocytes, ADAR-based RNA sensors for drug discovery, and quinazoline inhibitors penetrating the brain to block C797X double mutants. Together, these platforms illustrate convergent approaches to dismantle disease drivers at protein, immune, RNA, and signaling levels.

Interestingly, sorafenib-induced apoptosis in HepG2 cells was repressed by siADAR1, but this repression was not observed in HepG2 CYCS 3'-UTR-deleted cells. Collectively, this study clarified that ADAR1 upregulates CYCS translation by inhibiting stress granule formation and thereby can facilitate anticancer agent-induced apoptosis.

This study underscores the biological relevance of RNA editing in CRC, highlighting its impact on chemoresistance, the tumor microenvironment, and subtype-specific gene regulation. Our findings suggest that RNA editing represents a critical post-transcriptional regulatory layer in CRC and holds potential as a biomarker and therapeutic target.