Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy-lysosome pathway. This interaction results in the inhibition of plasma cell differentiation, thereby alleviating the progression of collagen-induced arthritis. Additionally, our investigation identifies Salvianolic acid B (SAB) as a potent small molecular glue-like compound that enhances the interaction between PRDX1 and DOK3, consequently impeding the progression of collagen-induced arthritis by inhibiting plasma cell differentiation. Collectively, these findings underscore the therapeutic potential of developing chemical stabilizers for the PRDX1-DOK3 complex in suppressing plasma cell differentiation for RA treatment and establish a theoretical basis for targeting PRDX1-protein interactions as specific therapeutic targets in various diseases.

Objective To investigate the efficacy of switching to co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/c/F/TAF) combined with sofosbuvir/velpatasvir (SOF/VEL) in the treatment of previously untreated chronic hepatitis C patients with HIV/HCV co-infection and the changes in blood lipid levels. Methods This prospective cohort study was conducted among 10 previously untreated chronic hepatitis C patients with HIV/HCV co-infection who attended Department of Infectious Diseases in Tangdu Hospital from July 2019 to May 2021 and achieved continuous HIV suppression after antiretroviral treatment (ART). As for anti-HIV therapy, the ART regimen was switched to the E/c/F/TAF regimen for 32 weeks, and for anti-HCV therapy, the SOF/VEL regimen was started since week 4 after switching and lasted for 12 weeks. Related indices were monitored before and after switching to E/c/F/TAF for anti-HCV therapy and SOF/VEL for anti-HCV therapy, including body weight, body mass index, HCV genotype, alpha-fetoprotein, liver stiffness measurement, CD4 + T cell count, CD4 + T/CD8 + T ratio, hepatic and renal function parameters, blood lipids, HIV RNA, HCV RNA, SVR12, SVR24, and adverse reactions. The Mann-Whitney U test was used for comparison of continuous data between two groups, and a Spearman correlation analysis was performed. Results After 4 weeks of treatment with E/c/F/TAF, 10 patients (HCV genotypes 2a and 1b) had HIV RNA below the lower limit of detection (20 IU/ml) and a significant reduction in albumin ( Z =-2.801, P =0.003 7), with the other indices remaining stable, and the patients reported significant improvements in the adverse events of anti-HIV therapy with the former ART regimen. After 4 weeks of E/c/F/TAF combined with SOF/VEL, the patients had HCV RNA below the lower limit of detection (15 IU/ml), and both SVR12 and SVR24 reached 100%; after 12 weeks of anti-HCV therapy, there were significant reductions in alanine aminotransferase ( Z =-2.732, P =0.004 8) and aspartate aminotransferase ( Z =-2.501, P =0.010 7) and significant increases in total cholesterol (TC) ( Z =-2.797, P =0.003 9) and low-density lipoprotein cholesterol (LDL-C) ( Z =-2.343, P =0.018 5), with a significantly positive correlation between them ( r =0.87, P < 0.001), and all the other indices were normal. Conclusion For previously untreated chronic hepatitis C patients with HIV/HCV co-infection, switching to E/c/F/TAF combined with SOF/VEL has good efficacy, tolerability, and safety, and the combination of the two regimens can avoid drug interaction, achieve a high HCV cure rate, and maintain HIV suppression. Transient increases in TC and LDL-C are observed during combination treatment, which suggests dyslipidemia caused by HCV infection and the pharmacological action of this regimen.

Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATP-competitive inhibitor of PGK1 with an affinity of K _d = 99.08 nmol/L. DC-PGKI stabilizes PGK1 in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition, DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages. Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium (DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.