AIM:This study aims to investigate the functions of interleukin-6(IL-6)/Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway in adenomyosis(ADM),and to assess the therapeutic potential of JAK2 inhibitor AG490.METHODS:(1)Neonatal female mice were randomly divided into 2 groups:control group and ADM group.An ADM mice model was established by tamoxifen.Additionally,Western blot was employed to detect the expression of IL-6/JAK2/STAT3 signaling pathway-related proteins.(2)Human endometrial adenocarcinoma Ishikawa cells were treated with AG490,and Western blot was performed to evaluate the expression of the proteins related to IL-6/JAK2/STAT3 signaling pathway,epithelial-mesenchymal transition(EMT),cell migration and cell proliferation.Besides,wound-healing and Transwell assays were carried out to investigate the cell migration and inva-sion.Colony formation and EdU assays were employed to investigate the cell proliferation,and flow cytometry analysis was performed to investigate the cell apoptosis.(3)The ADM mice were randomly divided into 2 groups:ADM group and AG490 group.The expression of IL-6/JAK2/STAT3 signaling pathway-related proteins in uterine tissues was detected by Western blot.Besides,Western blot and immunohistochemistry were employed to detect the expression of the proteins re-lated to cell EMT,migration and proliferation.Cell apoptosis in uterine tissues was detected by TUNEL assay.RE-SULTS:(1)The expression of IL-6/JAK2/STAT3 signaling pathway-related proteins exhibited an increasing trend in ADM mice(P<0.05).(2)Treatment with AG490 significantly suppressed the expression of IL-6/JAK2/STAT3 signaling pathway-related proteins in Ishikawa cells(P<0.05).The protein level of E-cadherin showed an increasing trend(P<0.01),while the expression levels of N-cadherin,vimentin and Slug showed a decreasing trend(P<0.05)in Ishikawa cells after AG490 treatment.Besides,the expression of MMP-2 and MMP-9 was down-regulated(P<0.05),and the capa-bilities of cell migration and invasion were suppressed in AG490-treated Ishikawa cells(P<0.05).The expression levels of Bcl-2 and cyclin D1 exhibited a decreasing trend(P<0.05),and the expression level of Bax increased(P<0.05)in Ishikawa cells after treatment with AG490.Additionally,AG490 inhibited Ishikawa cell proliferation,and enhanced the cell apoptosis(P<0.01).(3)The p-JAK2/JAK ratio and the IL-6 expression exhibited a decreasing trend in AG490 group(P<0.01).Moreover,the expression of E-cadherin was up-regulated(P<0.05),while the expression of N-cadherin,vi-mentin,Snail,Slug and Twist was down-regulated(P<0.05)in ADM mice after treatment with AG490.Compared with ADM group,the expression of MMP-2 and MMP-9 decreased in AG490 group(P<0.05),alongside the down-regulated Bcl-2/Bax ratio and PCNA expression(P<0.01).Besides,the cell apoptosis was enhanced by AG490.CONCLUSION:The IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in ADM and facilitates endometrial cell EMT,prolifera-tion,invasion and migration.Additionally,AG490 inhibits the progression of ADM by blocking the IL-6/JAK2/STAT3 sig-naling pathway.

AIM:This study aims to investigate the functions of interleukin-6(IL-6)/Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway in adenomyosis(ADM),and to assess the therapeutic potential of JAK2 inhibitor AG490.METHODS:(1)Neonatal female mice were randomly divided into 2 groups:control group and ADM group.An ADM mice model was established by tamoxifen.Additionally,Western blot was employed to detect the expression of IL-6/JAK2/STAT3 signaling pathway-related proteins.(2)Human endometrial adenocarcinoma Ishikawa cells were treated with AG490,and Western blot was performed to evaluate the expression of the proteins related to IL-6/JAK2/STAT3 signaling pathway,epithelial-mesenchymal transition(EMT),cell migration and cell proliferation.Besides,wound-healing and Transwell assays were carried out to investigate the cell migration and inva-sion.Colony formation and EdU assays were employed to investigate the cell proliferation,and flow cytometry analysis was performed to investigate the cell apoptosis.(3)The ADM mice were randomly divided into 2 groups:ADM group and AG490 group.The expression of IL-6/JAK2/STAT3 signaling pathway-related proteins in uterine tissues was detected by Western blot.Besides,Western blot and immunohistochemistry were employed to detect the expression of the proteins re-lated to cell EMT,migration and proliferation.Cell apoptosis in uterine tissues was detected by TUNEL assay.RE-SULTS:(1)The expression of IL-6/JAK2/STAT3 signaling pathway-related proteins exhibited an increasing trend in ADM mice(P<0.05).(2)Treatment with AG490 significantly suppressed the expression of IL-6/JAK2/STAT3 signaling pathway-related proteins in Ishikawa cells(P<0.05).The protein level of E-cadherin showed an increasing trend(P<0.01),while the expression levels of N-cadherin,vimentin and Slug showed a decreasing trend(P<0.05)in Ishikawa cells after AG490 treatment.Besides,the expression of MMP-2 and MMP-9 was down-regulated(P<0.05),and the capa-bilities of cell migration and invasion were suppressed in AG490-treated Ishikawa cells(P<0.05).The expression levels of Bcl-2 and cyclin D1 exhibited a decreasing trend(P<0.05),and the expression level of Bax increased(P<0.05)in Ishikawa cells after treatment with AG490.Additionally,AG490 inhibited Ishikawa cell proliferation,and enhanced the cell apoptosis(P<0.01).(3)The p-JAK2/JAK ratio and the IL-6 expression exhibited a decreasing trend in AG490 group(P<0.01).Moreover,the expression of E-cadherin was up-regulated(P<0.05),while the expression of N-cadherin,vi-mentin,Snail,Slug and Twist was down-regulated(P<0.05)in ADM mice after treatment with AG490.Compared with ADM group,the expression of MMP-2 and MMP-9 decreased in AG490 group(P<0.05),alongside the down-regulated Bcl-2/Bax ratio and PCNA expression(P<0.01).Besides,the cell apoptosis was enhanced by AG490.CONCLUSION:The IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in ADM and facilitates endometrial cell EMT,prolifera-tion,invasion and migration.Additionally,AG490 inhibits the progression of ADM by blocking the IL-6/JAK2/STAT3 sig-naling pathway.

Background/Aims: To evaluate the causal correlation between complement components and non-viral liver diseases and their potential use as druggable targets. Methods: We conducted Mendelian randomization (MR) to assess the causal role of circulating complements in the risk of non-viral liver diseases. A complement-centric protein interaction network was constructed to explore biological functions and identify potential therapeutic options. Results: In the MR analysis, genetically predicted levels of complement C1q C chain (C1QC) were positively associated with the risk of autoimmune hepatitis (odds ratio 1.125, 95% confidence interval 1.018–1.244), while complement factor H-related protein 5 (CFHR5) was positively associated with the risk of primary sclerosing cholangitis (PSC;1.193, 1.048– 1.357). On the other hand, CFHR1 (0.621, 0.497–0.776) and CFHR2 (0.824, 0.703–0.965) were inversely associated with the risk of alcohol-related cirrhosis. There were also significant inverse associations between C8 gamma chain (C8G) and PSC (0.832, 0.707–0.979), as well as the risk of metabolic dysfunction-associated steatotic liver disease (1.167, 1.036–1.314). Additionally, C1S (0.111, 0.018–0.672), C7 (1.631, 1.190–2.236), and CFHR2 (1.279, 1.059–1.546) were significantly associated with the risk of hepatocellular carcinoma. Proteins from the complement regulatory networks and various liver diseaserelated proteins share common biological processes. Furthermore, potential therapeutic drugs for various liver diseases were identified through drug repurposing based on the complement regulatory network. Conclusions Our study suggests that certain complement components, including C1S, C1QC, CFHR1, CFHR2, CFHR5, C7, and C8G, might play a role in non-viral liver diseases and could be potential targets for drug development.