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A FAPI-based small-molecule drug conjugate alleviates rheumatoid arthritis by targeting pathogenic FAPα-expressing fibroblasts

Acta Pharmacologica Sinica volume 47, pages 964–976 (2026)Cite this article

Abstract

The management of rheumatoid arthritis (RA) has advanced into the realm of targeted therapies; however, these therapies often lack tissue specificity and cause systemic adverse effects. Fibroblast-activating protein α (FAPα+) expressing fibroblast-like synoviocytes (FLSs) are critical pathogenic cell components in RA and are particularly abundant in inflamed joints, whereas they are minimal in other tissues. Consequently, FAPα+ FLSs are emerging as promising therapeutic targets for treating RA. However, strategies to specifically target FAPα+ FLSs in RA remain underdeveloped. To bridge this gap, we developed a novel compound, FAPI-Gly-Pro-MTX (FM), which integrates a FAPα+ tracer, FAPα inhibitor (FAPI), with the traditional drug methotrexate (MTX) via a glycine-proline dipeptide that can be cleaved by the dipeptidyl peptidase activity of FAPα. In an arthritis mouse model, FM selectively targeted FAPα+ FLSs in inflamed joints, facilitating the localized release of MTX and resulting in the significant alleviation of arthritis symptoms while minimizing systemic toxicity. Importantly, the presence of FAPI ensured that FM induced cell death specifically when FAPα+ FLSs were presented, thereby enhancing safety. Consequently, FM demonstrated considerable clinical potential as a safe and effective off-the-shelf therapeutic option for targeting FAPα+ FLSs in patients with RA.

a FAPα+ FLSs are induced by various inflammatory cytokines in inflamed joints and aggravate inflammation and bone destruction; b FM selectively delivers MTX to FAPα+ FLSs in RA-inflamed joints and minimizes off-target effects; c Conventional MTX administration lacks cell specificity, leading to systemic adverse effects.

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Fig. 1: FAPα expression was associated with pathogenic FLS phenotype and specially enriched in inflamed joints.
Fig. 2: FM structure and in vitro MTX release assay.
Fig. 3: FM selectively exerted cytotoxic effects when pathogenic FAPα+ FLS was presented.
Fig. 4: FM can target inflammatory joints and remain in joints for prolonged period in CIA mice.
Fig. 5: FM released MTX in inflamed joints and ameliorated inflammation and joint destruction in CIA mice.
Fig. 6: FM ameliorated bone destruction and decreased FAPα+ FLS in CIA mice.
Fig. 7: FM slightly increased Treg cells compared to MTX treatment in CIA mice.
Fig. 8: FM decreased MTX deposition in non-diseased organs.

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Acknowledgements

This work was supported by the Science Foundation of Fujian Province (Grant numbers 2023J06055, YL) (Grant number 2025J011438, HYQ); National Natural Science Foundation of China (Grant number 82471833, YL) (Grant number 82371802, GXS) and Xiamen Medical and health guidance project (Grant number 3502Z20244ZD1025, HYQ), (Grant number 3502Z20244ZD1016, YH); (Grant number 3502Z20244ZD1005, SJC).

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Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China

    Hong-yan Qian, Yan He, Chao-qiong Deng, Ao-di Wang, Yong-xin Ma, Yan Li, Shi-ju Chen, Xin-wei Zhang, Nasrullah Jan, Gui-xiu Shi & Yuan Liu

  2. Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen, 361000, China

    Hong-yan Qian, Yan He, Shi-ju Chen, Xin-wei Zhang, Gui-xiu Shi & Yuan Liu

  3. Xiamen Key Laboratory of Rheumatology and Clinical Immunology, Xiamen, 361000, China

    Hong-yan Qian, Yan He, Shi-ju Chen, Xin-wei Zhang, Gui-xiu Shi & Yuan Liu

  4. Research Center for Translational Medicine, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China

    Hong-jun Zhuang

  5. Department of Clinical Laboratory, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China

    Shi-peng Chen

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Contributions

Conceptualization: Yuan L, GXS; Data curation: HYQ, YH, CQD, ADW, YXM, Yan L; Formal analysis: HYQ, YH, HJZ; Funding acquisition: Yuan L, GXS, HYQ, YH, SJC; Methodology: HYQ, YH, CQD, ADW, YXM; Validation: CQD, ADW, YXM; Writing – original draft: Yuan L, HYQ, SJC, XWZ; Writing – review & editing: N Jan, SPC, Yuan L, GXS.

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Correspondence to Gui-xiu Shi or Yuan Liu.

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Qian, Hy., He, Y., Deng, Cq. et al. A FAPI-based small-molecule drug conjugate alleviates rheumatoid arthritis by targeting pathogenic FAPα-expressing fibroblasts. Acta Pharmacol Sin 47, 964–976 (2026). https://doi.org/10.1038/s41401-025-01680-x

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