Small-molecule targeting PKM2 provides a molecular basis of lactylation-dependent fibroblast-like synoviocytes proliferation inhibition against rheumatoid arthritis.

Fibroblast-like synoviocytes (FLS) play an important role in rheumatoid arthritis (RA)-related swelling and bone damage. Therefore, novel targets for RA therapy in FLS are urgently discovered for improving pathologic phenomenon, especially joint damage and dyskinesia. Here, we suggested that pyruvate kinase M2 (PKM2) in FLS represented a pharmacological target for RA treatment by antimalarial drug artemisinin (ART). We demonstrated that ART selectively inhibited human RA-FLS and rat collagen-induced arthritis (CIA)-FLS proliferation and migration without observed toxic effects. In particular, the identification of targets revealed that PKM2 played a crucial role as a primary regulator of the cell cycle, leading to the heightened proliferation of RA-FLS. ART exhibited a direct interaction with PKM2, resulting in an allosteric modulation that enhances the lactylation modification of PKM2. This interaction further promoted the binding of p300, ultimately preventing the nuclear translocation of PKM2 and inducing cell cycle arrest at the S phase. In vivo, ART obviously suppressed RA-mediated synovial hyperplasia, bone damage and inflammatory response to further improve motor behavior in CIA-rats. Taken together, these findings indicate that directing interventions towards PKM2 in FLS could offer a hopeful avenue for pharmaceutical treatments of RA through the regulation of cell cycle via PKM2 lactylation.

CDYL knockdown reduces glioma development through an antitumor immune response in the tumor microenvironment.

Gliomas are highly prevalent and aggressive brain tumors. Growing evidence shows that epigenetic changes are closely related to cancer development. Here we report the roles of Chromodomain Y-like (CDYL), an important epigenetic transcriptional corepressor in the central nervous system in glioma progression. We found that CDYL was highly expressed in glioma tissues and cell lines. CDYL knockdown decreased cell mobility in vitro and significantly reduced tumor burden in the xenograft mouse in vivo. RNA sequencing analysis revealed the upregulation of immune pathways after CDYL knockdown, as well as chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 12. The immunohistochemistry staining and macrophage polarization assays showed increased infiltration of M1-like tumor-associated macrophages/microglia (TAMs) while decreased infiltration of M2-like TAMs after CDYL knockdown in vivo and in vitro. Following the in situ TAMs depletion or CCL2 antibody neutralization, the tumor-suppressive role of CDYL knockdown was abolished. Collectively, our results show that CDYL knockdown suppresses glioma progression, which is associated with CCL2-recruited monocytes/macrophages and the polarization of M1-like TAMs in the tumor microenvironment, indicating CDYL as a promising target for glioma treatment.