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Objective: To assess the impact of the IFIT3/TBK1 signalling pathway in activating plasmacytoid dendritic cells (pDCs) and its role in the development of SSc. Methods: Utilized single‐cell RNA sequencing (scRNA‐seq) and high‐throughput transcriptome RNA sequencing to reveal the differential abundance of pDCs and the role of the key gene IFIT3 in SSc. Conducted in vitro cell experiments to evaluate the effect of IFIT3/TBK1 signalling pathway intervention on pDC activation cytokine release and fibroblast function. Constructed an IFIT3−/− mouse model using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein 9 (Cas9) gene editing to assess the potential benefits of intervening in the IFIT3/TBK1 signalling pathway on skin and lung fibrosis in the SSc mouse model. Results: The IFIT3/TBK1 signalling pathway plays a crucial role in activating pDCs, with IFIT3 acting as an upstream regulator of TBK1. Intervention in the IFIT3/TBK1 signalling pathway can inhibit pDC activation cytokine release and impact fibroblast function. The IFIT3−/− mouse model shows potential benefits of targeting the IFIT3/TBK1 signalling pathway in reducing skin and lung fibrosis in the SSc mouse model. Conclusion: This study provides new insights into potential therapeutic targets for SSc, highlighting the critical role of the IFIT3/TBK1 signalling pathway in SSc development. Highlights: This study elucidates the pivotal role of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc).This study identified the key regulatory gene involved in systemic sclerosis (SSc) as IFIT3.This study has found that IFIT3 functions as an upstream regulatory factor, activating TBK1.This study provides Evidence of the regulatory effects of the IFIT3/TBK1 pathway on plasmacytoid dendritic cells (pDCs).This study validated the therapeutic potential using the IFIT3−/− mouse model. [ABSTRACT FROM AUTHOR]

Human umbilical cord mesenchymal stem cells (hUCMSCs) exhibit potent self-renewal and multilineage differentiation characteristics. They have garnered substantial attention within the domain of regenerative medicine owing to their therapeutic potential, such as in tissue repair, regeneration, immunomodulation, anti-inflammation, angiogenesis, wound healing, neuroprotection, and neuroregeneration. The process of fate determination is initiated by multiple signaling molecules. During development and tissue homeostasis, the Notch signaling pathway assumes a pivotal function in cell differentiation and the renewal of stem cells. A growing body of research has revealed that the Notch signaling pathwayplays a pivotal role in hUCMSC proliferation and differentiation. The latest progress concerning the crucial functions of the Notch signaling pathway in maintaining homeostasis and determining the cell fate of hUCMSCs is summarized. Furthermore, the authors also summarized the mediators related to the Notch signaling pathway in hUCMSC differentiation, as well as the pathway alterations and mechanisms involved in hUCMSC therapy., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)