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Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review)

  • Authors:
    • Chengzhi Cong
    • Yuan Wang
    • Jian Liu
    • Chao Jin
  • View Affiliations / Copyright

    Affiliations: Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230031, P.R. China
    Copyright: © Cong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 205
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    Published online on: May 21, 2026
       https://doi.org/10.3892/mmr.2026.13915
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Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. As the disease progresses, joint deformity, loss of joint function and disability may occur, thereby seriously affecting the quality of life of patients, as well as their physical and mental health. The PI3K/AKT signaling pathway serves a critical role in regulating inflammatory responses, cell survival and gene expression in RA. The present review aimed to summarize how PI3K/AKT modulates the expression of key genes involved in RA pathogenesis, including cytokines and non‑coding RNAs. In addition, the crosstalk between PI3K/AKT and other signaling pathways, as well as the potential therapeutic strategies currently available for RA, are discussed.
View Figures

Figure 1

Schematic diagram of the PI3K/AKT
signaling pathway in the pathogenesis of rheumatoid arthritis.
Upstream activators, including growth factors and chemokines, act
through RTKs and GPCRs to activate class IA and class IB PI3K,
leading to the conversion of PIP2 to PIP3, a process antagonized by
PTEN. Downstream activation of AKT regulates cell proliferation and
immune inflammation through multiple effectors, including the
Ras/RAF/MEK/ERK and mTOR pathways. FOXO1, Forkhead box O1; GPCR,
G-protein-coupled receptor; GSK-3β, Glycogen synthase kinase-3β;
mTORC1, Mammalian target of rapamycin complex 1; PDPK1,
3-phosphoinositide-dependent protein kinase 1; PIP2,
Phosphatidylinositol 4,5-bisphosphate; PIP3, Phosphatidylinositol
3,4,5-trisphosphate; RTK, Receptor tyrosine kinase. Created with
BioGDP.com (104).

Figure 2

Post-transcriptional and epigenetic
modification mechanisms of the PI3K/AKT pathway in rheumatoid
arthritis. This diagram illustrates how activated AKT modulates
transcription factors and downstream effectors, including NF-κB,
FoxO, mTOR and GSK-3β, to regulate the expression of
pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6 and IL-8, as
well as MMPs (MMP-3 and MMP-9), thereby promoting cell
proliferation and inflammation. FoxO, Forkhead box O; GSK-3β,
Glycogen synthase kinase-3β; Created with BioGDP.com (104).

Figure 3

Crosstalk between the PI3K/AKT
signaling pathway and ncRNAs in rheumatoid arthritis. ncRNAs,
including miR-124a, miR-21, lncRNA THRIL, lncRNA H19 and
circRNA_09505, modulate PI3K/AKT signaling at multiple levels.
miR-124a directly targets the PI3K p110α subunit (PIK3CA) to
inhibit FLS proliferation, whereas miR-21 suppresses PTEN to
promote FLS proliferation. lncRNA THRIL activates PI3K/AKT
signaling, thereby increasing IL-1β and MMP-3 expression levels;
lncRNA H19 functions as a competing endogenous RNA; and
circRNA_09505 sponges miR-6089 to enhance AKT1 expression in
macrophages. circRNA, circular RNA; FLS, fibroblast-like
synoviocyte; lncRNA, long ncRNA; miR, microRNA; PDK1,
phosphoinositide-dependent kinase 1.Created with BioGDP.com
(104).

Figure 4

Integrated crosstalk between the
PI3K/AKT signaling pathway and other key signaling pathways in RA.
Interactions between PI3K/AKT and other major signaling pathways in
RA, including apoptosis-related regulators (ATP/P2X7R, NLRP3, FoxO
and BRCA1), inflammatory pathways (NF-κB, JAK/STAT and
MAPK/ERK/JNK/p38), Notch signaling (NICD/CSL/Hey/DTX), and
transcriptional outputs (ELK, ATF, AP, STAT, CREB and MEF).
Together, these signaling networks contribute to bone erosion,
metabolic alterations and cell migration in RA. FoxO, forkhead box
O; IKK, inhibitor of κB kinase; NICD, Notch intracellular domain;
NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; PDK1,
phosphoinositide-dependent kinase 1; RA, rheumatoid arthritis.
Created with BioGDP.com (104).
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Copy and paste a formatted citation
Spandidos Publications style
Cong C, Wang Y, Liu J and Jin C: Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review). Mol Med Rep 34: 205, 2026.
APA
Cong, C., Wang, Y., Liu, J., & Jin, C. (2026). Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review). Molecular Medicine Reports, 34, 205. https://doi.org/10.3892/mmr.2026.13915
MLA
Cong, C., Wang, Y., Liu, J., Jin, C."Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review)". Molecular Medicine Reports 34.1 (2026): 205.
Chicago
Cong, C., Wang, Y., Liu, J., Jin, C."Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review)". Molecular Medicine Reports 34, no. 1 (2026): 205. https://doi.org/10.3892/mmr.2026.13915
Copy and paste a formatted citation
x
Spandidos Publications style
Cong C, Wang Y, Liu J and Jin C: Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review). Mol Med Rep 34: 205, 2026.
APA
Cong, C., Wang, Y., Liu, J., & Jin, C. (2026). Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review). Molecular Medicine Reports, 34, 205. https://doi.org/10.3892/mmr.2026.13915
MLA
Cong, C., Wang, Y., Liu, J., Jin, C."Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review)". Molecular Medicine Reports 34.1 (2026): 205.
Chicago
Cong, C., Wang, Y., Liu, J., Jin, C."Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review)". Molecular Medicine Reports 34, no. 1 (2026): 205. https://doi.org/10.3892/mmr.2026.13915
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