This review aims to elucidate the role of the PI3K/AKT signaling pathway in the pathogenesis of rheumatoid arthritis (RA), with particular emphasis on its regulatory mechanisms governing key gene expression, inflammatory responses, and cell survival. By synthesizing current evidence, the review seeks to clarify how this pathway contributes to synovial inflammation, joint destruction, and disease progression, and to identify potential therapeutic targets arising from its molecular network.

A comprehensive literature review was performed by systematically searching peer‑reviewed studies focusing on the PI3K/AKT pathway in RA. The analysis encompasses experimental data from in vitro models, animal studies, and clinical samples, with an emphasis on the pathway’s modulation of cytokines, chemokines, and non‑coding RNAs (including microRNAs and long non‑coding RNAs). In addition, the crosstalk between PI3K/AKT and other major signaling cascades—such as NF‑κB, MAPK, and JAK/STAT—was examined to construct an integrated view of the signaling network operating in RA synovial tissues and immune cells.

Accumulating evidence indicates that the PI3K/AKT signaling pathway is aberrantly activated in RA, particularly in fibroblast‑like synoviocytes, macrophages, and T cells. This hyperactivation promotes the sustained expression of pro‑inflammatory cytokines (e.g., TNF‑α, IL‑6, and IL‑1β) and matrix‑degrading enzymes, thereby perpetuating synovitis and cartilage destruction. Moreover, the pathway modulates the expression of various non‑coding RNAs, which act as either positive or negative regulators of inflammatory gene expression. Notably, PI3K/AKT exhibits extensive crosstalk with other pathways: cross‑activation with NF‑κB amplifies inflammatory responses, while reciprocal regulation with MAPK and JAK/STAT pathways fine‑tunes cell proliferation and survival. These interactions create a complex signaling network that sustains the chronic inflammatory state and drives resistance to apoptosis in activated synoviocytes.

The PI3K/AKT signaling pathway serves as a central hub integrating inflammatory signals and cell fate decisions in RA. Its multifaceted regulation of cytokines, non‑coding RNAs, and synergistic interactions with other pathways underscores its potential as a promising therapeutic target. Future strategies targeting key nodes within this network—either alone or in combination with existing disease‑modifying antirheumatic drugs—may offer more effective and personalized approaches for managing RA. Further research is warranted to translate these mechanistic insights into clinical applications and to overcome challenges such as pathway redundancy and off‑target effects.