Aberrant protein secretion is a central driver of tissue inflammation and destruction in rheumatoid arthritis (RA). While RA fibroblast-like synoviocytes (FLSs) exhibit prominent endoplasmic reticulum (ER) and Golgi, the mechanism underlying their excessive protein secretion is not fully understood. Here, we identified the deficiency of de novo NAD+ synthesis enzyme, quinolinate phosphoribosyltransferase (QPRT), as a significant abnormality in RA synovium. QPRT loss counterintuitively inflates NAD+ in the trans-Golgi network (TGN) while decreasing NAD+ in the cytoplasm, ER and cis/medial-Golgi. QPRT knockdown promoted Golgi membrane expansion and epithelial-to-mesenchymal-transition (EMT)-associated secretome production in RA FLSs by suppressing TGN-residing PARP12, resulting in mTORC1-mediated protein translation and Golgi expansion. Furthermore, QPRT gene therapy restored NAD+ balance, corrected Golgi dysfunction, reduced cytokine production, and improved RA severity in mouse models. These findings underscore QPRT's role in coordinating protein secretion and the regulatory dynamics of compartmentalized NAD+, proposing QPRT targeting as a therapeutic strategy for inflammatory, secretory and Golgi-related diseases.

L.W.N. and Q.Y. are inventors of two patent applications filed by Shenzhen Institute of Advanced Technology. Patent application numbers are CN202310841862.6 and PCT/CN2023/137624.

This work is supported by the National Key R&D Program of China (2021YFF1200300), National Natural Science Foundation of China (22207118, 22307135), Shenzhen Science and Technology Program (JCYJ20220818100804009), the Natural Science Foundation of Guangdong Province (2023A1515010715), R&D plan in key areas of Guangdong Province (2023B1111030002), Research Projects on Key Areas of General Colleges and Universities, Department of Education of Guangdong Province (2022ZDZX2071), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study used openly available human data that were originally located at: Gene Expression Omnibus (GEO) The Cancer Genome Atlas (TCGA) clinical proteomic tumor analysis consortium (CPTAC) Human synovial tissue and blood samples were collected from individuals undergoing knee joint replacement surgery at the Shenzhen Second People's Hospital in China. The participants with rheumatoid arthritis fulfilled the American College of Rheumatology and the European League Against Rheumatism diagnostic criteria and provided written informed consent. The study was approved by the Ethics Committee of the Second People's Hospital of Shenzhen (2023-157-01YJ).

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All data produced in the present study are available upon reasonable request to the authors