Therapeutic Targeting of Apoptosis-Driven Inflammation in Rheumatoid Arthritis: A Biochemical and Molecular Modeling Approach Using Plant-Derived Compounds

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, joint destruction, and resistance to apoptosis in fibroblast-like synoviocytes and immune cells. This apoptotic imbalance promotes unchecked cell proliferation and invasive pannus formation, contributing to disease progression. Current therapies predominantly target inflammatory pathways, often overlooking the crucial role of restoring apoptosis. Our study explores the potential of plant-derived phytochemicals to modulate both inflammation and apoptosis in RA. Using an integrated computational approach, 12 bioactive compounds were evaluated for their interactions with key apoptosis-associated proteins MMP9, SRC, and EGFR, which are known to influence cell survival, matrix degradation, and invasive behavior in RA. Molecular docking revealed that quercetin, apigenin, resveratrol, and naringenin exhibit strong binding affinities with MMP9, SRC, and EGFR. These interactions were further supported by stable molecular dynamics (MD) simulations, indicating favorable binding stability and structural compatibility. The modulation of these targets suggests a dual therapeutic effect—suppressing inflammation and restoring apoptotic signaling, thus potentially reversing pathological synovial hyperplasia. This study underscores the importance of targeting apoptosis-related proteins in RA and highlights plant-derived compounds as promising candidates for multi-target therapeutic development. By addressing both inflammatory and apoptotic dysregulation, these natural agents may offer a safer and more effective strategy for RA management.