The research team led by Professor Zhongyu Xie from Sun Yat-sen University revealed a new mechanism by which Pim1 regulated Th17 cell differentiation through mitochondrial metabolism. Through molecular docking screening, they identified Nilotinib as an effective candidate drug for the treatment of inflammatory arthritis by targeting Pim1. The relevant achievement has been published in Research (DOI: 10.34133/research.1137) with the title "Pim1 Serves as a Therapeutic Target for Inflammatory Arthritis via Mitochondrial Metabolism and Th17 Cell Differentiation."

Research Background
Inflammatory arthritis, mainly including rheumatoid arthritis and ankylosing spondylitis, is a group of chronic and progressive osteoimmune-related diseases characterized by joint bone destruction, which severely threaten patients’ health and quality of life. The core pathological mechanism of inflammatory arthritis is closely related to the abnormal differentiation of Th17 cells. Th17 cells secrete pathogenic cytokines such as IL-17A and IL-17F, recruit and regulate the functions of other inflammatory cells, thereby mediating cartilage erosion and bone destruction. Clarifying the mechanism of the abnormal Th17 cell differentiation in inflammatory arthritis will help to better understand its pathogenesis and explore new treatment options.

Pim1 is a serine/threonine protein kinase that participates in the occurrence and development of osteoimmune-related diseases by mediating cytokine-dependent signal transduction in T cells. Although previous studies have reported that Pim1 could affect the differentiation potential of T cells, its pathogenic role and specific mechanism in inflammatory arthritis, as well as whether specific targeting of Pim1 has therapeutic potential for osteoimmune-related diseases, remain unclear.

Research Progress
Elevated Expression of Pim1 is a Key Cause of Abnormal Differentiation of Th17 Cells in Inflammatory Arthritis
The research team found that the protein level of Pim1 was significantly upregulated in CD4⁺T cells in the peripheral blood and inflamed joints of patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), which was closely associated with the increased proportion of Th17 cells. By constructing mice with specific knockout of Pim1 in CD4⁺T cells (Pim1 cKO), the team found that Pim1 cKO mice exhibited significantly reduced manifestations of inflammatory arthritis, including joint swelling, inflammatory infiltration, cartilage destruction, and bone erosion, along with a marked decrease in Th17 cell proportion and significant reduction in IL-17A expression (Figure 1).

Pim1 Promotes Th17 Cell Differentiation by regulating Mitochondrial Metabolism
Further exploration by the team showed that Pim1 promoted mitochondrial calcium influx by phosphorylating mitochondrial calcium uptake protein 1 (MICU1), thereby activating mitochondrial oxidative phosphorylation to provide energy and metabolic support for Th17 cell differentiation. In vitro experiments confirmed that elevated expression of Pim1 significantly promoted Th17 cell differentiation and the expression of Th17 cell-related pathogenic genes, and these effects were blocked by mitochondrial calcium influx inhibitors (Figure 2).

Pim1-targeting Nilotinib Can Significantly Inhibit Th17 Cell Differentiation and Alleviate Inflammatory Arthritis
Using molecular docking and dynamic simulation technology, the team screened Nilotinib from the FDA-approved drug library as a specific inhibitor of Pim1. This drug could stably bind to the active pocket of Pim1, inhibit its kinase activity, and suppress Th17 cell differentiation. In vivo experiments showed that Nilotinib could significantly inhibit Th17 cell differentiation and alleviate joint swelling, inflammatory infiltration, cartilage destruction, and bone erosion in mice, while these effects were blocked in Pim1 cKO mice (Figure 3).

Future Outlook
Further optimizing the administration regimen and improving the safety and efficacy evaluation of Nilotinib are expected to promote the translational application of Nilotinib in the clinical treatment of inflammatory arthritis. Meanwhile, developing a delivery system for Pim1 inhibitors specifically targeting CD4⁺T cells is expected to further enhance their therapeutic specificity, providing more treatment options for inflammatory arthritis and other Th17 cell-related autoimmune diseases.

The complete study is accessible via DOI: 10.34133/research.1137