Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.

Targeted protein degradation in cancers:Orthodox PROTACs and beyond

Targeted protein degradation(TPD)is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors.Proteolysis-targeting chimera(PROTAC)technology can be used to target proteins by hijacking the ubiquitin-proteasome system.Conceptually,PROTAC aims to target the“undruggable”majority of proteins in the human proteome.Through constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades,TPD has expanded from theoretical studies to clinical strategies,with practical applications in oncological,immunological,and other diseases.In this review,we introduce the mechanisms,features,and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical trials.We also discuss PROTAC derivatives and other TPD strategies,such as lysosome-targeting chimeras,autophagy-targeting chimeras,and molecular glue strategies.Collectively,the studies summarized herein support the full potential of TPD in the biomedical industry.