Available online 7 March 2024, 106557

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There is growing evidence of an elevated risk of lung cancer in patients with rheumatoid arthritis. The poor prognosis of rheumatoid arthritis-associated lung cancer and the lack of therapeutic options pose an even greater challenge to the clinical management of patients. This study aimed to identify potential molecular targets associated with the progression of rheumatoid arthritis-associated lung cancer and examine the efficacy of naringenin nanoparticles targeting cyclin B1. Mendelian randomizatio analysis revealed that rheumatoid arthritis has a positive correlation with the risk of lung cancer. Cyclin B1 was significantly upregulated in patients with rheumatoid arthritis-associated lung cancer and was significantly overexpressed in synovial tissue fibroblasts. Furthermore, the overexpression of cyclin B1 in rheumatoid arthritis fibroblast-like synoviocytes, which promotes their proliferation and fibroblast-to-myofibroblast transition, can significantly contribute to the growth and infiltration of lung cancer cells. Importantly, our prepared naringenin nanoparticles targeting cyclin B1 effectively attenuated proliferation and fibroblast-to-myofibroblast transition by blocking cells at the G2/M phase. In vivo experiments, naringenin nanoparticles targeting cyclin B1 significantly alleviated the development of collagen-induced arthritis and lung orthotopic tumors. Collectively, our results reveal that naringenin nanoparticles targeting cyclin B1 can suppress the progression of rheumatoid arthritis-associated lung cancer by inhibiting fibroblast-to-myofibroblast transition. These findings provide new insights into the treatment of rheumatoid arthritis-associated lung cancer therapy.

Section snippetsINTRODUCTION

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation, predisposition to joint damage and deformity, and extra-articular involvement (Figus et al., 2021, Sparks, 2019). It has been reported that the more severe and active a rheumatic disease is, the more likely it is to induce cancer (Baecklund et al., 2006, Strangfeld et al., 2010, Wang et al., 2023). Many epidemiological studies have established a strong link between RA and increased risk of

Mendelian Randomization (MR) Analysis

MR analysis was performed using genome-wide association study (GWAS) summary data obtained from the IEU Open GWAS database. The present study incorporated pooled information from GWAS involving 212,453 patients with RA from East Asia and 374,687 patients with LC from Europe. Instrumental variables (IVs) encompassing single nucleotide polymorphisms (SNPs) closely associated with RA were selected for this analysis. Subsequently, a range of MR analysis techniques, including inverse-variance

RA Genetically Increases LC Risk

First, 12 SNPs that were strongly linked to RA (P < 5 × 10−8) with no linkage disequilibrium (LD) (R2 < 0.001) were chosen as the IVs for subsequent MR analysis. The F-statistics of these SNPs were all > 100, indicating their effectiveness in predicting LC incidence. Both MR-Egger and IVW showed P value > 0.05 in Cochran’s Q-test, indicating that 12 genetic variants of RA did not exhibit significant heterogeneity in the LC. Therefore, all the selected RA‐associated genetic variants can be

DISCUSSION

In this study, we found that increased genetic susceptibility to RA is a strong risk factor for LC, and that CCNB1 is upregulated in the peripheral blood, synovial tissue, and lung tissue of patients with RA-LC. Specifically, the upregulation of CCNB1 in RA-FLS had a notable impact on the proliferation, migration, and invasiveness of co-cultured lung cancer cells. Furthermore, excessive expression of CCNB1 contributed to cell proliferation, transformation of FMT, and evasion of apoptosis in

CONCLUSION

Collectively, these results suggest that RA genetically increases the risk of LC. Mechanistically, this study demonstrated that RA-FLS with high CCNB1 expression play an important role in the joint-lung axis of RA-LC. NARNPs attenuated the progression of RA-LC by impeding the FMT transition of RA-FLS through targeted inhibition of CCNB1 (Fig. 7). Therefore, the targeting of CCNB1 by NARNPs is a promising approach for RA-LC treatment.

Ethics approval

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Qilu Hospital of Shandong University (KYLL-202210-069-1). Informed consent was obtained from all subjects involved in the study. The animal study protocol was approved by the Ethics Committee on Animal Experiment of Shandong University Qilu Hospital (DWLL-2023-066).

FUNDING

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82272410, 81972005 and 82302605); Natural Science Foundation of Shandong Province (Grant No. ZR2021QH329); Taishan scholar program of Shandong Province (Grant Nos. tstp20221156 and tsqn202306346); Major Scientific and Technological Innovation Project of Shandong Province (Grant No. 2021CXGC010603).

CRediT authorship contribution statement

Xilong Wang: Writing – original draft, Visualization, Validation, Software. Hongxing Wang: Writing – review & editing, Resources, Conceptualization. Yi Zhang: Writing – review & editing, Resources, Conceptualization. Guixi Zheng: Supervision. Xin Zhang: Supervision. Xiaohan Li: Validation, Software. Peng Su: Methodology, Data curation. Zhipu Liu: Software, Methodology. Na Zhao: Software, Methodology. Xiaoyu Zhang: Validation, Software, Investigation, Data curation.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

ACKNOWLEDGMENTS

We appreciate the participation of all the patients and healthy volunteers in this study.

AUTHOR CONTRIBUTION

Y.Z. and H.W. designed the study. Y.Z., G.Z. and X.Z. supervised the experiments. X.W. and X.Z. performed the majority of the experiments. N.Z. and X.L. assisted in collection of experimental materials. P.S. provided human samples. Z.L. provided key reagents or experimental advice. X.W. and H.W. analyzed the data. X.W. wrote the manuscript and Y.Z. and H.W. revised the manuscript. All authors read and

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