UBE2O reduces the effectiveness of interferon-α via degradation of IFIT3 in hepatocellular carcinoma.

Interferon (IFN) exerts its effects through interferon-stimulated genes (ISGs), but its efficacy is limited by interferon resistance, which can be caused by the ubiquitination of key proteins. UBE2O was initially identified as a promising therapeutic target based on data from the TCGA and iUUCD 2.0 databases. Through the inhibition of UBE2O, interferon α/ß signaling and overall interferon signaling were activated. Integrating data from proteomic, mass spectrometry, and survival analyses led to the identification of IFIT3, a mediator of interferon signaling, as a ubiquitination substrate of UBE2O. The results of in vitro and in vivo experiments demonstrated that the knockdown of UBE2O can enhance the efficacy of interferon-α by upregulating IFIT3 expression. K236 was identified as a ubiquitination site in IFIT3, and the results of rescue experiments confirmed that the effect of UBE2O on interferon-α sensitivity is dependent on IFIT3 activity. ATO treatment inhibited UBE2O and increased IFIT3 expression, thereby increasing the effectiveness of interferon-α. In conclusion, these findings suggest that UBE2O worsens the therapeutic effect of interferon-α by targeting IFIT3 for ubiquitination and degradation.

Avatrombopag for the treatment of thrombocytopenia induced by chemotherapy in patients with solid tumors: A multicenter, open-label, single-arm trial.

Objective: To explore the effect and safety of avatrombopag for chemotherapy-induced thrombocytopenia (CIT). Methods: This multicenter, open-label, single-arm trial enrolled CIT patients in eight centers from October 2020 to April 2021. The participants received avatrombopag tablets 60 mg once a day for 5-10 days. The main endpoint was the proportion of patients with platelet count ≥100×109/L or increased by ≥ 50×109/L or increased by ≥ 100% in the cycle after the start of treatment. Results: Seventy-four participants were enrolled with a mean age of 59.8 ± 11.62.2% were males. The cumulative effective rate (any criteria) was 70.3% at 4 weeks. 42 (56.8%) achieved platelet count ≥100×109/L, 44 (59.5%) increased by ≥ 50×109/L, and 27 (36.5%) increase by ≥ 100% from baseline. The duration of grade III and IV platelet reduction was 4.2 ± 5.3 days. The time of PLT recovery to ≥75×109/L was 9.4 ± 6.6 days. The time of PLT recovery to ≥100×109/L was 10.2 ± 6.4 days. The platelet count nadir was 57.9 ± 45.3×109/L. The most common adverse events were nausea (8.1%), fatigue (5.4%), and abdominal pain (1.4%). There were no cases of fever, headache, or peripheral edema. Conclusion: Although it was a single-arm trial without a control group, the application of avatrombopag in patients with CIT can increase the platelet count of the patients compared with baseline. Avatrombopag is safe and tolerable. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04609891?term=04609891&draw=2&rank=1, identifier [NCT04609891].