Background: Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its radiosensitive effects in nasopharyngeal carcinoma (NPC). However, the detailed mechanism of afatinib-mediated sensitivity to radiation is still obscure in NPC. Methods: Quantitative phosphorylated proteomics and bioinformatics analysis were performed to illustrate the global phosphoprotein changes. The activity of the CD44-Stat3 axis and Epithelial-Mesenchymal Transition (EMT)-linked markers were evaluated by Western blotting. Wound healing and transwell assays were used to determine the levels of cell migration upon afatinib combined IR treatment. Cell proliferation was tested by CCK-8 assay. A pharmacological agonist by IL-6 was applied to activate Stat3. The xenograft mouse model was treated with afatinib, radiation or a combination of afatinib and radiation to detect the radiosensitivity of afatinib in vivo. Results: In the present study, we discovered that afatinib triggered global protein phosphorylation alterations in NPC cells. Further, bioinformatics analysis indicated that afatinib inhibited the CD44-Stat3 signaling and subsequent EMT process. Moreover, functional assays demonstrated that afatinib combined radiation treatment remarkably impeded cell viability, migration, EMT process and CD44-Stat3 activity in vitro and in vivo. In addition, pharmacological stimulation of Stat3 rescued radiosensitivity and biological functions induced by afatinib in NPC cells. This suggested that afatinib reversed the EMT process by blocking the activity of the CD44-Stat3 axis. Conclusion: Collectively, this work identifies the molecular mechanism of afatinib as a radiation sensitizer, thus providing a potentially useful combination treatment and drug target for NPC radiosensitization. Our findings describe a new function of afatinib in radiosensitivity and cancer treatment.

Acute liver failure (ALF) is a life-threatening clinical syndrome characterized by high-grade inflammation and multi-organ failure. Our previous study shows that targeting the M2 isoform of pyruvate kinase (PKM2) to inhibit macrophage inflammation may be a promising strategy for ALF treatment. however, the mechanism by which PKM2 regulates the inflammatory response is unclear. Here we demonstrate that PKM2 contributes to ALF by modulating NLRP3-mediated pyroptosis activation in liver macrophages. The specific knockout of PKM2 in myeloid cells reduces mortality and alleviates hepatic injury in D-galactosamine/LPS-induced ALF mice. Single-cell transcriptome analysis suggests that NLRP3 inflammasome activation of macrophages involves in ALF, knockout of PKM2 in macrophages reduces the expression of NLRP3, and activation of pyroptosis. Pharmacological inhibition of the PKM2 nuclear translocation, but not glycolytic activity, protects mice from ALF. Pharmacological and genetic inhibition of PKM2 attenuates NLRP3-mediated pyroptosis activation and consequently reduces the release of IL-1β and IL-18 by macrophages. Mechanistically, PKM2 translocates into the nucleus and combines with STAT3, enhancing its phosphorylation and recruitment to the NLRP3 promoter region, thereby increasing NLRP3 expression. This work defines PKM2 acts as an important nonmetabolic regulator of NLRP3 that modulates pyroptosis activation in macrophages and guides future therapeutic strategies development for ALF.

Background: Hepatitis B surface antigen (HBsAg) loss is durable in some patients with chronic hepatitis B (CHB) after pegylated interferon α (Peg-IFNα)–based treatment. However, factors associated with durable HBsAg loss are not clear. This study aimed to investigate predictors of durable HBsAg loss. Methods: Patients with CHB and HBsAg loss were enrolled from 2018 to 2022 in the Everest Project and followed up for 48 weeks after Peg-IFNα therapy discontinuation. Sustained response (SR) was defined as durable HBsAg loss with or without hepatitis B surface antibody (HBsAb) appearance at the end of follow-up, while recurrence was characterized by HBsAg reversal and/or detectable HBV DNA during follow-up. Data on the risk factors of durable HBsAg loss were analyzed between SR and recurrence. Results: A total of 1046 patients were included in this study: 822 with SR and 224 with recurrence. At end of follow-up, 1.41% (224/1046) had relapsed. HBsAb at the end of Peg-IFNα treatment and Peg-IFNα consolidation therapy time were associated with SR (area under the receiver operating curve [AUROC], 0.709 [P < .001]; AUROC, 0.620 [P < .001], respectively), with the optimal cutoff values of 25.67 IU/L and 12.786 weeks. The prediction model was based on HBsAb at end of treatment and consolidation therapy time, and AUROCs of the model for predicting efficacy in the training and validation sets were 0.7071 and 0.736. Conclusions: HBsAb at end of treatment and Peg-IFNα consolidation therapy time are potential predictors of durable HBsAg loss.

BACKGROUND Acute decompensation (AD) of cirrhosis is associated with high short-term mortality, mainly due to the development of acute-on-chronic liver failure (ACLF). Thus, there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is released from activated innate immune cells and correlated with various inflammatory processes. AIM To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis. METHODS A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort (n = 309) and validation cohort (n = 133). Demographic and clinical data were collected, and serum sTREM-1 was measured at admission. All enrolled patients were followed-up for at least 1 year. RESULTS In patients with AD and cirrhosis, serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver, coagulation, cerebral and kidney failure. A new prognostic model of AD (P-AD) incorporating sTREM-1, blood urea nitrogen (BUN), total bilirubin (TBil), international normalized ratio (INR) and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease (MELD), MELD-sodium (MELD-Na), chronic liver failure-consortium (CLIF-C) ACLF and CLIF-C AD scores. Additionally, sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up. The ACLF risk score incorporating serum sTREM-1, BUN, INR, TBil and aspartate aminotransferase levels was established and significantly superior to MELD, MELD-Na, CLIF-C ACLF, CLIF-C AD and P-AD in predicting risk of ACLF development. CONCLUSION Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.

The situation regarding Hepatocellular carcinoma (HCC) is severe, with high incidence and mortality rates worldwide. Abnormal expression of long noncoding RNAs (LncRNAs) has been implicated in the progression of malignant tumors. Although there are reports on LncRNA FTX (Lnc-FTX) in HCC, the findings are still contradictory, leaving its role unclear. This research aims to examine the relationship between Lnc-FTX expression and clinical prognosis in HCC, assess its impact on HCC cell biological functions, and elucidate the underlying mechanisms involved. Our findings demonstrate that patients in the high-expression group exhibit more severe TNM staging and poorer overall survival (OS) rates based on data from HCC patients in cohort 1 (n=27). Lnc-FTX expression is upregulated according to both the GSE 77314 and TCGA databases. This suggests that Lnc-FTX may serve as a potential prognostic biomarker for HCC. Overexpressed level of Lnc-FTX promotes proliferation, migration, and invasion while reducing the apoptotic rate in Hep3B and MHCC-LM3 cells. Conversely, the knockdown of Lnc-FTX yields opposite effects. RNA pulldown assay and mass spectrometry reveal that Lnc-FTX combines with RNA binding motif protein X-linked (RBMX), which in turn enhances the RNA stability of Lnc-FTX. Additionally, Lnc-FTX can sponge miR-374a-3p, thereby targeting High mobility group box 1 protein (HMGB1). In summary, high expression of Lnc-FTX possesses clinical value in predicting poor prognosis in HCC. As an oncogene, it promotes the malignant functions of HCC through the RBMX/Lnc-FTX interaction and the Lnc-FTX/miR-374a-3p/HMGB1 signaling pathway.