The Kunduan Yimu decoction improves rheumatoid arthritis by targeting microRNA-155-5p to enhance autophagy and reduce inflammation.

BACKGROUND

The pathogenesis of rheumatoid arthritis (RA) involves dysregulated inflammation and oxidative stress, necessitating novel therapeutic strategies. The traditional drug methotrexate (Methotrexate) has limitations, and the potential of the compound Kunduan Yimu Decoction (KDYMD) and the role of microRNA-155-5p (miRNA-155-5p) require further investigation.

METHODS

In a randomized 12-week comparative study, treatment-naïve RA patients (n = 66) were assigned to KDYMD (daily oral decoction) or oral MTX (10 mg/week), while age- and sex-matched healthy controls (n = 33) served as baseline comparators. PBMCs/plasma were collected at baseline (week 0) and post-treatment (week 13). Key assessments included inflammatory cytokine and oxidative stress marker levels via enzyme-linked immunosorbent assay and biochemical assays; joint pathology via micro- computed tomography and histology (hematoxylin and eosin, Safranin O-Fast Green); miR-155-5p expression via RT-qPCR; cellular phenotypes via Cell Counting Kit-8, transwell, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays; autophagy via transmission electron microscopy and western blot (LC3, Beclin-1, and p62); and Phosphoinositide 3-kinase (PI3K)/ Protein kinase B (AKT)/ Nuclear factor kappa B (NF-κB) pathway activity via western blot. Gain- and loss-of-function experiments were performed for both miR-155-5p and PI3K modulators.

RESULTS

KDYMD effectively ameliorated RA symptoms in RA patients and CIA mice by reducing joint inflammation, bone erosion, cartilage degradation, synovial hyperplasia, and inflammatory/oxidative stress markers. This demonstrates that KDYMD is as effective as MTX. Importantly, unlike MTX, KDYMD significantly suppressed elevated miR-155-5p expression in both RA patient PBMCs and CIA mice. In RA-FLSs, KDYMD inhibited malignant phenotypes (proliferation, migration, and invasion) and promoted apoptosis. Mechanistically, KDYMD enhanced autophagy flux and mitigated inflammation and oxidative stress. This was linked to KDYMD's inhibition of the PI3K/AKT/NF-κB pathway. Furthermore, RA-FLS growth, inflammation, and oxidative stress were exacerbated by miR-155-5p overexpression and attenuated by its inhibition; KDYMD inhibit the effects of the miR-155-5p mimic and enhanced the effects of the inhibitor. KDYMD requires suppression of miR-155-5p to inhibit PI3K/AKT/NF-κB signaling and subsequently induce protective autophagy.

CONCLUSIONS

KDYMD exhibits anti-arthritic effects similar to those of MTX by uniquely suppressing miR-155-5p This suppression is central to KDYMD's mechanism, inhibiting PI3K/AKT/NF-κB signaling, enhancing autophagy, and ultimately reducing inflammation, oxidative stress, and synovial hyperplasia. KDYMD represents a promising alternative therapeutic candidate for RA.