Rituximab-Chidamide combination chemotherapy enhances autophagy to overcome drug resistance in diffuse large B-cell...

Diffuse large B-cell lymphoma (DLBCL) is a challenging malignancy, particularly when resistance to standard therapies such as Rituximab develops. This study investigates the combined therapeutic effects of Rituximab and Chidamide on DLBCL, focusing on drug resistance mechanisms and autophagy regulation. Using high-throughput proteomics and transcriptomic analyses, key proteins and signaling pathways were identified. BTG1 emerged as a signature gene, while autophagy-related genes such as BECN1, ATG5, HSPA8, PTEN, and MAPK8 were highlighted as pivotal players. In vitro experiments using Rituximab-sensitive and -resistant DLBCL cell lines (Raji and Raji-4RH) demonstrated that Chidamide significantly inhibited cell proliferation in a dose- and time-dependent manner, induced G0/G1 phase arrest, and enhanced autophagy. Mechanistically, Chidamide upregulated histone acetylation and autophagy-related proteins while reducing p62 levels, synergistically promoting autophagy with Rituximab. In vivo mouse models confirmed the combined treatment's efficacy in suppressing tumor growth. These findings suggest that the BTG1/BECN1/ATG5 signaling axis plays a critical role in enhancing autophagy and reversing Rituximab resistance. The combination of Chidamide and Rituximab presents a promising therapeutic strategy, offering new insights into overcoming drug resistance in DLBCL.